In the economic field, debt economy is a common and complicated economic model. Simply put, debt economy is to obtain funds by borrowing and issuing bonds to promote economic development. This economic model is very common in the modern economic system, and many countries, enterprises and even individuals will use this method to meet their own capital needs.

At the national level, the government may issue treasury bonds to raise funds for infrastructure construction and social welfare. For example, some countries will build highways, railways and other transportation facilities on a large scale, and these projects need a lot of capital investment. The government will attract investors to buy them by issuing government bonds, thus obtaining funds to support the development of the projects. For enterprises, in order to expand production scale and carry out technological innovation, they will also borrow money from banks or issue corporate bonds. Like some emerging science and technology enterprises, in the process of developing new products, they need a lot of money for scientific research investment and equipment purchase, so they will choose debt financing to solve the funding problem.

Triangular debt is a special and thorny phenomenon in debt economy. Triangular debt refers to the debt chain formed by mutual arrears of payment between enterprises. In this case, enterprise A owes money to enterprise B, enterprise B owes money to enterprise C, and enterprise C may owe money to enterprise A, forming a complex debt cycle.

The influence of triangular debt is various. For enterprises, it will seriously affect the capital turnover of enterprises. When an enterprise’s payment is in arrears by other enterprises, its own funds cannot be withdrawn in time, which leads to the enterprise’s failure to pay the payment of raw material suppliers and the wages of employees on time, thus affecting the normal production and operation of the enterprise. In the long run, it may also lead to the reduction of the production scale of enterprises and even face the risk of bankruptcy.

From the macro-economic perspective, triangular debt will affect the operational efficiency of the whole economy. A large number of enterprises fall into the dilemma of triangular debt, which will make the capital flow in the market not smooth and hinder the rational allocation of resources. Debt disputes between enterprises may also trigger a series of legal proceedings and increase the transaction cost of society.

In order to understand the debt economy and triangular debt more intuitively, the following table is used for comparison:

In short, debt economy and triangular debt are both important issues that need to be paid attention to in economic operation. Correctly understanding and handling them is of great significance for maintaining economic stability and healthy development.

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foreword　 　

At present, tumor immunotherapy is in the ascendant, and one of the most effective treatment strategies is adoptive cell transfer therapy (ACT). Chimeric antigen receptor (CAR) and engineered T cell receptor (TCR) are the main adoptive T cell immunotherapy in recent years. TCR engineering T cells express tumor antigen-specific receptors, and their α chains and β chains are produced by high-quality and high-affinity antigen-specific T cell clones.

TCR molecule belongs to a superfamily of immunoglobulin, which consists of two covalently bound polymorphic subunits, each of which is antigen-specific, and they are related to at least four different types of signal transduction chains. In order to activate T cells, there must be interaction between TCR and MHC.

The interaction between TCRs and pMHC(peptide-MHC) determines the fate of immature thymocytes, which is very important for the survival of naive T cells. Therefore, TCR-T immunotherapy technology activates the host’s immune system through effective interaction with MHC, especially class II molecules, which are specifically recognized by TCR-T cells and CAR-T cells. TCR-T cells can recognize tumor-specific antigens in cells, while CAR-T cells mainly recognize tumor-specific antigens on the surface. This makes TCR-T cells more effective in tumor treatment.

At present, some new technologies and tools are being applied to TCR-T, which is helpful to improve the efficacy and safety of TCR-T therapy. TCR-T cell therapy is showing great potential for anti-tumor therapy.

　 Comparison between CAR-T and TCR-T

In ACT therapy, TCR-T and CAR-T cells have been successfully used in the clinical treatment of solid tumors.

CAR contains single chain antibody targeting tumor antigen, transmembrane domain and intracellular activation domain of CD3ζ. In this way, the engineered CAR can recognize specific tumor-associated antigens, and CAR can bind untreated tumor surface antigens without MHC treatment.

The first generation of CAR-T cells showed limited expansion and relatively short persistence, and the "second generation" CAR-T added costimulatory receptors CD28, 4-1BB/CD137 and OX40. These costimulatory receptors are added to the CD3ζ domain of CAR-T cells, thus promoting a more powerful and lasting T cell response. The third generation CARs combines two co-stimulatory signals (CD28 and 4-1BB) at the same time, which has better amplification and longer persistence than the second generation CARs.

On the contrary, TCR is an α/β heterodimer that binds to MHC antigen complex. Compared with TCR, CARs has some disadvantages in identifying tumor antigens, such as extratumoral toxicity. Compared with CARs, TCRs has some structural advantages in T cell-based therapy, such as more subunits (10: 1) in its receptor structure, more tyrosine-based activation motifs (ITAMs) in immune receptors (10: 3), less dependence on antigens (1: 100), and more costimulatory receptors (CD3, CD4, CD28, etc.). TCR with a low MHC affinity range (104-106M-1) can effectively activate T cells, whereas CARs needs a higher affinity range (106-109M-1).

Therefore, CAR-mediated cytotoxicity depends on higher density of cell surface antigens. In addition, T-cell/antigen interaction IS initiated in the structure of immune synapse (IS), in which TCR presents an annular region with peripheral LFA-1 adhesion, while CAR presents a diffuse LFA-1 distribution without annular region. Therefore, TCR-IS is slower but lasts longer than CAR-IS. At the same time, CAR-T cells show faster killing function and migrate to the next tumor target (serial killing), which is in sharp contrast to TCR-T cells’ prolonged signal transduction and killing time.

Recombination TCRs 　

TCR is one of the most complex receptors in human body. It contains six different receptor subunits, which have a very wide range of functions in T cells. The change of TCR of tumor infiltrating lymphocytes (TILs) significantly affects tumor-specific T cells. Among them, the change of TCR is helpful to the proliferation of T cells, and the diversity of TCR is related to the anti-tumor effect.

TCR engineering of TIL is one of the best treatment methods for tumors. TCR consists of α chain and β chain bound to peptide -MHC ligand, signal subunits (,γ and δ) of CD3 complex and CD3ζ homodimer. Except CD3ζ, all subunits have extracellular immunoglobulin (Ig) domain. Based on these structures, new technologies using engineering TCR include ImmTAC, TRuCs and TAC.

Immune mobilization monoclonal t cell receptor (ImmTAC)

ImmTACs is designed using engineered, soluble and affinity-enhanced monoclonal TCRs(mTCRs). ImmTACs is basically a fusion protein, which combines the engineering TCR targeting system and single chain antibody fragment (scFv) effector function. In the construction of ImmTACs, TCR can recognize peptides from intracellular targets presented by human leukocyte antigen (HLA).

ImmTAC specifically targets HLA- peptide complexes on the surface of tumor cells, and promotes T cell-mediated effector function through the interaction between scFv antibody fragments and CD3. ImmTAC also activates CD8+T cells in a dose-dependent manner, and can effectively redirect and activate CD8+ and CD4+ cells. ImmTAC shows multifunctional reaction by secreting various cytokines, such as TNF-α, IFN-γ, IL-6, MIP1α-β and IFN-γ inducible protein 10.

In addition, selecting the appropriate target antigen is the key to ImmTACs, and mass spectrometry and MHC polymer technology are helpful to identify the appropriate antigen. It is worth noting that TCR engineered T cells also show unexpected targeted toxicity. Generally speaking, ImmTACs has been proved to enhance the anti-tumor response of TCR-T cells, but its safety needs further study.

T cell receptor fusion structure

T cell receptor fusion structure (TRuCs), an antibody binding domain fused with T cell receptor subunits, is designed to effectively recognize tumor surface antigens. TRuCs is composed of specific antibodies targeting tumor-associated antigens fused to the extracellular N- terminal of five TCR subunits (TCRα, TCRβ, CD3, CD3γ and CD3δ), which provides new targeting specificity and HLA-independent target cell clearance for engineered T cells and can be activated by corresponding target cells.

Compared with the second generation of CAR-T cells, this method shows better anti-tumor effect. In addition, TRuCs dominates all the signal mechanisms of TCR complex, while CARs only uses the limited signal of the isolated intracellular segment of CD3ζ.

T cell antigen coupling agent (TAC)

T cell antigen coupling agent is another engineered TCR cell, which can induce more effective anti-tumor response and reduce toxicity in an MHC-independent way. TAC chimeric protein can form TCR/CD3 complex and get more T cell responses by binding to CD3 domain.

The activity of TAC receptor is closely related to the selection of CD3 binding domain. For example, a single chain antibody from OKT3(muromonab-CD3) has lower cytokine production and cytotoxicity compared with UCHT1, which may lead to substantially different functional results. Compared with the second generation of CARs, T cells engineered with TAC gene are not only beneficial to the greater infiltration in solid tumors after adoption, but also reduce the expansion and extratumoral toxicity of T cells in healthy tissues expressing antigens.

Workflow of TCR-T cell therapy 　

In order to isolate therapeutic TCR, antigen-specific T cells must be isolated from the blood of patients or healthy blood donors and amplified in vitro with specific peptide antigens and cytokines (such as IL-2 and IL-15). This process needs to determine the specific tumor-related peptide targets that can be safely targeted to patients in advance. After selecting the target antigen, different methods can be used to screen TCR with the required high affinity and tumor specificity. Pre-clinical safety testing is also necessary to ensure the minimum off-target effect and cross-reactivity of isolated high affinity TCR. Viral vectors are usually used to genetically modify autologous patient T cells to express the proven therapeutic TCR, and then transfuse it back into patients.

Determine the target antigen

Melanoma antigen 1(MART-1) recognized by T cells is the first tumor-related antigen targeted in TCR-T clinical trials. After this breakthrough, TCR-T therapies for various tumor antigens have been developed, including TCR-T therapies for MAGE-A3, MAGE-A4, GD2, mesothelin, gp100, MART1, AFP, CEA, NY-ESO-1 and viral peptides derived from HPV and EBV. Among them, NY-ESO-1 has been proved to be one of the most promising targets of TCR-T cells, and it has achieved success in the treatment of synovial sarcoma, with an objective effective rate of 67%.

The ideal TCR-T target antigen shows the following characteristics: (1) the ability to induce immune response; (2) It is related to driving tumor phenotype (such as oncogene) to reduce the risk of antigen loss and tumor immune escape; And (3) expression on tumor stem cells to promote permanent tumor eradication.

Identification method of tumor-associated antigen

High-resolution mass spectrometry (MS) has been proved to be the most powerful Qualcomm method to promote the direct identification of HLA-I binding peptides from tumor cells. In this method, HLA-I/ peptide complexes are separated from tumor tissues or cell lines by immunoprecipitation (IP), and then the binding peptide antigens are separated from HLA-I molecules and antibodies for IP by fully washing and applying acidic elution buffer. This strategy allows each tumor sample to identify thousands of validated peptide targets, and has been used to identify HLA-I ligands of glioblastoma (GB), melanoma, renal cell carcinoma (RCC) and colorectal cancer (CRC).

Identification method of new tumor antigen

Although MS-based technology can be used to identify new antigens, it is more difficult to identify them, especially for tumor samples with limited size, because of their relatively low abundance and limited sensitivity of MS. However, the development of new generation sequencing technology is helpful to identify and locate such tumor targets. All-exon DNA sequencing, combined with computational prediction algorithm, allows to identify specific genetic changes in cancer cells, which can produce mutant peptides and present them on tumor HLA-I molecules.

All somatic mutant genes can be analyzed by computer to predict the potential high affinity epitopes that may bind to HLA-I molecules of patients, so as to be recognized by T cells. With the use of large MS elution peptide database, HLA-I peptide binding prediction algorithm is constantly updated and improved, and other prediction algorithms try to consider biological variables related to the complexity of intracellular processes.

Another commonly used method is tumor RNA sequencing, which allows the selection of new antigens with the highest transcriptional expression. It is worth noting that although these prediction methods usually show very good accuracy in identifying presented and highly immunogenic new antigens, the number of new antigen targets they usually predict is 1 to 2 orders of magnitude higher than the actual number of real targets.

Discovering new antigens by trogocytosis is a new method in recent years. Trogocytosis is a biological phenomenon in the process of cell combination, in which cells share and transfer membrane and membrane-related proteins. Li et al. found that T cell membrane proteins were specifically transferred to tumor target cells, which presented homologous HLA-I/ peptide complexes. Using these T cell-target cell interactions, they created a new antigen discovery system by incubating T cells expressing orphan TCR with homologous target cells. By transferring fluorescent markers from T cells to target cells, this method can isolate these target cells and sequence homologous TCR ligands, thus establishing a new antigen library.

Isolation of tumor-specific T cells and TCR

Using HLA-I polymer, single cell TCR sequencing or antigen-negative humanized mice, tumor-reactive T cells and TCR can be identified from autologous, allogeneic or xenogeneic cell banks.

Using HLA-I multimer method, antigen-specific CD8+T cells can be directly separated by multimer staining and flow cytometry. Before isolating the paired full-length TCR sequences, these polyclonal T cells were tested for homologous peptide recognition and anti-tumor function. TCR with high affinity and specificity can be obtained by using a highly sensitive PCR-based single cell TCR analysis method (TCR-SCAN).

Another method uses humanized mouse TCR gene bank, which will not cause T cell clone deletion or tolerance in humans. Therefore, Li et al. used the whole human TCRα/β gene locus and chimeric HLA-A2 transgene to construct transgenic mice to isolate human TCR against human TAA.

Single cell sequencing method represents a more promising method to isolate tumor-specific TCR coding genes by Qualcomm method. Using RNA bait libraries targeting each individual V and J element in TCRα and TCRβ loci, TCR coding genomic elements can be selectively isolated from excised genomic DNA(gDNA) fragments for subsequent paired terminal deep sequencing. This makes it possible to identify antigen-specific TCR from human materials or oligoclonal T cell populations of TCR humanized mice.

Infantile T cells can also be used as TCR sources for TCR-T therapy. TAA and new antigen-specific T cells can be derived and amplified from low-frequency precursors in peripheral blood of cancer patients, and can be reinfused or used as the source of antigen-specific TCR. Because cancer patients usually show immunosuppression or dominant T cell tolerance, the original sequence of HLA-I matched healthy donors also represents a reliable source, because it has a huge diversity of TCR sequences, and theoretically T cells have any antigen specificity, including new tumor antigens. A Qualcomm-quantity technology platform has been developed to find the original sequence, so as to quickly and effectively identify the rare but valuable TCR for personalized adoptive T cell therapy.

Cloning of TCR

Most TCR-based gene therapy methods rely on in vitro transduction of T cells with viral vectors, and adenovirus is the earliest vector used for gene therapy. However, due to their inability to integrate transgenes into the host genome, TCR expression will be lost during T cell proliferation. In addition, the immune genetic characteristics of adenovirus also limit its application as a gene therapy vector. In contrast, retroviruses show greater prospects as gene transfer vectors, because they can infect a variety of cells and have the ability to insert transgenes into the host genome, thus making the ectopic TCRα/β chain stably expressed.

Retroviral vectors derived from γ -retroviruses such as mouse leukemia virus (MLV) have been widely used for gene transfer into human T cells. This method has been used to transfer various genes, including suicide gene, TCR and CARs. The main disadvantage is that they cannot transduce non-proliferative target cells, which excludes the application of resting T cells in TCR-T therapy. In addition, retrovirus insertion mutation may cause potential side effects.

Recently, lentiviral vectors (LV) have attracted more attention as gene transfer vectors, because they can transfer genes into mitotic and non-splinter cell. Various techniques, such as Golden Gate cloning and LR cloning, are usually used to construct a vector for inserting TCRα/β gene.

Adeno-associated virus (AAV) is another widely used virus vector. Compared with adenovirus vector, AAV has lower immunogenicity and wider cell tropism, so it has been widely used in tumor gene therapy. In order to promote the integration of transgenes, people have developed self-complementary AAV vector (scAAV) to make AAV independent of the complementary strand synthesis of host cells. scAAV is more effective than traditional AAV in preclinical model.

At the same time, some non-viral gene editing methods have also been developed. MRNA electroporation has been proved to achieve transient expression of TCR and CAR, thus minimizing the risk of persistent virus components. Clinical data show that both TCR-T and CAR T cells modified by mRNA are feasible and safe, and there is no obvious evidence that they have non-targeted toxicity to normal tissues. However, the lack of continuous TCR expression may limit the curative effect and require repeated infusion. In addition, the non-viral sleeping beauty retrotransposon system is also used for the transduction of TCR and CARs.

Gene editing can insert large gene fragments into target cells specifically and efficiently through homologous directional repair (HDR). TCR-T cells developed by CRISPR/CAS9 have been proved to specifically recognize tumor antigens in vitro and induce a productive anti-tumor response in vivo.

Verification method of TCR

After TCR cloning, extensive preclinical verification is needed to prove the specificity and safety of engineered TCR-T cells. Verification includes evaluating the affinity of TCR by titration of homologous peptide antigens and measuring the killing effect of a group of HLA-I matched tumor cell lines. If there is no such tumor cell line, the target cells can transductively express related antigens and related HLA-I molecules. The new antigen can also be expressed in autologous antigen presenting cells to evaluate the antigen reactivity of TCR.

The safety test includes testing the ability of candidate TCR-T to identify HLA-I matching primary tissues, so as to ensure that there is no normal tissue as the target, which may lead to non-targeted toxicity. In at least two clinical trials of TCR-T cell therapy, there was a cross reaction between normal brain cells and heart cells, which led to the death of patients. These test results emphasize the importance of extensive safety tests before TCR enters clinical trials.

Safety of TCR-T 　

The ACT of TCR-T cells showed high tumor killing, but some serious adverse events also appeared in some clinical studies. It is very important to optimize TCR affinity in engineered T cells, and receptor affinity can determine the safety and effectiveness of T cell therapy. In terms of curative effect, affinity TCR interaction is enough to activate T cells, but strong affinity is needed to maintain the expansion of T cells.

In phase I/II ACT clinical trials, engineered T cells with low affinity show safer characteristics, but their anti-tumor response is weak. By identifying the TCR-pMHC interaction of T cells, engineered T cells can be divided into high affinity type and low affinity type. In addition, some technologies have been developed to improve the safety of TCR-T.

The safety switch mechanism based on engineered T cells is an attractive strategy. Thymidine kinase gene from herpes simplex virus type I (HSV-TK) is one of the most common suicide genes.

Although HSV-TK shows safety in cell-based immunotherapy, it is necessary to introduce phosphorylated nucleoside analogues. Another safer induced T cell safety switch is called inducible caspase-9(iC9). IC9 is a modified human FK binding protein, which can be activated by a small molecule compound AP1903, and this process depends on the mitochondrial apoptosis pathway.

The immunogenicity of iC9 suicide gene is low, and the immune response to transgenic cells is reduced. IC9-based safety switch has been proved to be more potential for cell therapy than previous suicide genes.

Clinical status of TCR-T cell therapy 　

As of August 9, 2021, there are 175 studies using TCR-T therapy in ClinicalTrials, 71 of which are specific TCR for specific TAA or new antigen, and 32 studies have been completed. NY-ESO-1 is the most common targeted antigen, which is expressed in many cancers, including myeloma and melanoma. Other tumor testis-associated antigens, such as PRAME and MAGE proteins, melanoma differentiation antigens MART-1 and gp100, and recent cancer drivers, such as WT1, KRAS and TP53, are also popular TCR-T targets.　 　 　 　 　 　 　 　 　 　 　

A total of 83 sponsors/collaborators initiated or participated in the research of TCR-T cell therapy, including the National Institutes of Health (NIH), government organizations, industries and universities/academic institutions. At present, the National Cancer Institute (NCI) has supported 53 TCR-T projects, accounting for 20% of all ongoing projects.

Among the 29 pharmaceutical companies developing TCR-T therapy, GlaxoSmithKline and Adaptimunime initiated the most clinical trials, with 11 and 7 respectively. Recently, a phase 1 clinical trial (NCT02858310) of TCR-T cells targeting human papillomavirus (HPV)-16 E7 protein in the treatment of metastatic human papillomavirus-related epithelial cancer was reported. In this study, 6 of the 12 patients who received treatment showed objective clinical response and observed steady tumor regression. This is a landmark clinical trial of TCR-T cell therapy, which proves that targeted virus antigen has good clinical effect on patients with virus-related cancer. Other viral antigens explored as TCR targets include HPV-E6 protein, antigens from Epstein-Barr virus (EBV) and human endogenous retrovirus (HERV) targets, such as Herv-E.

MART-1 and NY-ESO-1 TCR-T therapy targeting TAAs also showed clinical efficacy in advanced melanoma, myeloma and non-small cell lung cancer. The total effective rate (ORR) of TCR-T clinical trial is between 0 and 60%. It is worth noting that most of these TCR-T clinical trials only enrolled a small number of patients (2 to 25), so ORR may not be statistically accurate. Therefore, larger-scale phase II and III clinical trials are needed to confirm the actual clinical efficacy of these TCR-T therapies.

Challenges and potential solutions of TCR-T cell therapy 　

Although immunotherapy based on TCR-T cells has shown certain clinical efficacy in most patients receiving treatment, it still faces many challenges in many fields. These challenges include: (1) Immunotoxicity caused by targeting normal tissues; (2) The expression of TCR in engineered T cells is insufficient or transient; (3)T cell exhaustion and dysfunction; (4) tumor immune escape, and (5) most cancer patients lack effective tumor-specific antigens as targets. Overcoming these challenges will be the key to greater clinical success in the future.　 　 　 　 　 　　

Discovery of new targets

At present, the target of peptide antigen for effective and safe immunotherapy of TCR-T is very limited. At present, most of the targets used are TAA. Although it is up-regulated in tumor tissues, it still maintains a low level of expression in normal tissues, which may lead to autoimmune toxicity. Therefore, the new antigen seems to be the safest target for TCR-T cancer treatment. However, the main challenges of developing new antigens in TCR-T clinic include: (1) the mutation of new antigens is individualized to a great extent, and there are differences among cancer patients, so it is difficult to develop widely used immunotherapy products; (2) The expression of new antigens in tumor tissues is often heterogeneous.

Nevertheless, recent reports have highlighted the emergence of new immunogenic antigens widely shared by tumor cells, including mutated KRAS and TP53. Many other studies have also demonstrated the immunogenicity of shared new antigens that can be used to generate potential therapeutic tumor-specific TCR. With the development of next generation sequencing technology, especially single cell DNA sequencing, transcriptome sequencing and mature in vitro verification methods, TCR-T immunotherapy targeting personalized new antigens may become a popular cancer treatment method in the next few years. In addition, the emerging TAA class, such as carcinoembryonic antigen, may also constitute a feasible target for the future development of TCR-T.

Maximize therapeutic TCR expression

The correct pairing of transgenic α and β chains is one of the main challenges that hinder the development of TCR-T cells. Since each transduced T cell includes two endogenous TCR chains and two transformed TCR chains, heterodimers with unknown specificity can lead to potential autoimmune consequences. Another related problem is that improper α/β chain TCR pairing will compete for CD3 complex, thus reducing the surface expression and signal transduction of therapeutic TCR.

There are several methods to properly pair the transduced TCR chains, including: (1) the constant region of partially murine TCR; (2) adding cysteine residues to promote the introduction of disulfide bonds in TCR chains; (3) changing the secondary structure of the constant region of endogenous TCR; (4) adding a signal domain to the intracellular part transduced with TCR; (5) Introducing TCR-α/β chain into substitute effector cells or constructing single-stranded TCR.

Methods to enhance the expression of therapeutic TCR include: (1) codon optimization of TCR-α and TCR-β chain transgene, and (2) changing the configuration of TCR-α/TCR-β vector to optimize expression.

Reduce adverse events

Usually, targeting non-tumor toxicity is the main key obstacle of TAA, and this risk urges researchers to study common new antigens more carefully. At present, several oncogene hot spot mutations are being studied as potential TCR targets, such as phosphoinositide -3- kinase (PI3K), KRAS and TP53. In addition, genetically engineered TCR-T cells with suicide genes are an important safety measure. Obviously, it is very important to develop reliable, identifiable, personalized, highly specific and immunogenic tumor antigen targets to reduce adverse events related to TCR-T cell therapy.

Graft-versus-host disease of allogeneic T cells

Using allogeneic T cells is a very promising scheme, which can overcome manufacturing problems, patient-related immune cell defects and treatment delays. In order to use allogeneic T cells, it is necessary to control graft-versus-host disease caused by transduced allogeneic reactive lymphocytes and rejection of engineered lymphocytes by host immune system.

The deletion of endogenous TCR gene, HLA-I locus or CD52 molecule is one of the strategies to avoid the failure of TCR-T transplantation, which can be achieved by many methods, such as gene editing or using siRNA. In addition, pluripotent stem cell technology is also considered as a potential solution.

　 summarize

In recent years, engineered T cells have shown excellent curative effect in the treatment of hematological tumors. TCR regulation is very important for T cell reactivation, immune response and its clinical effect on foreign antigens. TCR-T cells have incomparable advantages over CAR-T cells, and show great potential in preclinical and clinical research.

However, there are still several key challenges to improve the anti-tumor efficacy of TCR-T immunotherapy, including how to safely increase the affinity of therapeutic TCR, how to identify the common tumor-specific antigen and TCR in the patient population, and how to regulate the expression of TCR and achieve the best function. The solution of these problems will help to give full play to the potential of TCR-T cell therapy and bring hope to cancer patients to relieve their pain.

References:

1.Engineered TCR-T CellI mmunotherapy in Anticancer Precision Medicine: Pros and Cons. Front Immunol.　2021; 12: 658753.

2. Evolution of CD8+　T Cell Receptor(TCR) Engineered Therapies for the Treatment of Cancer. Cells.　2021 Sep; 10(9): 2379.

[Original of Truck House] Because pulling agricultural and sideline products can enjoy high-speed and free policy treatment, many card friends are also more willing to pull green links, but we should keep our eyes open about pulling green links.

Since it is a "green channel", there must be many restrictions. It is impossible for all agricultural products to take the green channel. Recently, card friends in Shaanxi have suffered in this respect.

Recently, when a netizen dragged Apple through Shaanxi Ankang Expressway toll station, the toll collector said that the card friend’s vehicle could not enjoy the green channel treatment. Although the load of the vehicle met the requirements of Lutong, the toll must be paid in full.

Here, many card friends are puzzled. Ran He is listed in the catalogue of fresh agricultural products. Why does Ankang toll collector decide that the car apple does not belong to Lutong? Is this apple kicked out of the catalogue of agricultural products by Ankang?

The toll collector said that it is true that apples are green products, but the apples on the car have rotted in a large area and do not meet the definition of "fresh".freshIs the first condition to take the green link.Since you don’t meet the requirements, why can you enjoy green treatment?

The staff of Shaanxi Traffic and Transportation Service Hotline responded to the incident, saying that there is no dispute that apples belong to Lutong products. According to the on-site toll collector’s inspection, the apples loaded on the vehicle are all rotten apples, commonly known as "falling fruit". Therefore, even if the load of the whole vehicle is within the standard range, the cargo occupies more than 80% of the car volume, but because the fruits on the vehicle are rotting in a large area and are very stale, it is compliant not to let Lutong go.

The staff of Shaanxi Expressway Baihe Management Office introduced that enjoying the green channel policy refers to fresh vegetables and fruits, and the staff checked the vehicles, and the loaded goods (apples) had obvious rot.It does not meet the requirements of "liveliness" stipulated in the document, so it is feasible not to give green channel treatment.

According to the spirit of the document "Notice on Further Optimizing the Green Passage Policy of Fresh Agricultural Products Transportation" issued by the three ministries and commissions, fresh agricultural products enjoying the "green passage" policy refer to fresh vegetables, fruits, fresh aquatic products, live livestock and poultry, fresh meat, eggs and milk. If it is found that it is mixed or counterfeit and does not meet the policy requirements, it needs to be handled according to the regulations.

That is to say, the toll collectors have the right to inspect the vehicles carrying Lutong. As long as the loaded goods do not meet the requirements and specifications in the Catalogue of Fresh Agricultural Products, or the bearing quality does not meet the minimum load requirements of the documents, they are not allowed to take the green channel and must pay the toll.

● 　Postscript

Not all green products are green links. There used to be pineapple, pineapple and cherry cherries, but now there are fresh and rotten ones. I wonder what card friends think about the fact that rotten fruits are not green links. You can make your voice heard in the comments section. (Text/Wei Qingbo Source/Shaanxi Expressway Baihe Management Office)

1111 Super Shopping Carnival Feast, reduced by 100 at 599, sent to Kajia jackets at 1800, and found more good goods at Kajia Mall: https://j.youzan.com/k9OEp8.

Since the Eighth Five-Year Plan, the Tobacco Monopoly Bureau of Hanshou County, Changde has actively explored and innovated the ways, contents and forms of popularizing the law, carried out in-depth publicity for consumers, retailers and minors, and promoted the effectiveness of tobacco publicity and education under the rule of law.

Explain the law to consumers and improve the awareness of consumer rights protection.

(The staff of Hanshou County Bureau introduces the identification skills of true and false cigarettes to consumers)

"This is a fake cigarette? What do you think is no different from real cigarettes? How can you tell? "

As soon as the publicity booth of Hanshou Tobacco Monopoly Bureau was set up, enthusiastic people gathered around to ask questions. The staff of the county bureau gave patient answers to the preaching, while making detailed comparisons with the real and fake cigarette exhibits, and carefully answered the knowledge points of identification of real and fake cigarettes for the onlookers by means of "you ask me and answer me".

Over the years, Hanshou County Bureau has taken various effective forms to carry out regular publicity on legal popularization. In 2024 alone, it has held similar legal popularization activities for more than 10 times, distributed more than 300 tobacco monopoly legal popularization brochures printed by the county bureau, such as "Quick Identification of True and False Cigarettes", "How much do you know about the harm of fake cigarettes? Stay away from new disguised drugs-"E-cigarettes on the top ",and printed QR codes on brochures and exhibition boards to realize the popularization and dissemination of legal popularization audiences.

Send it to French retailers to improve the standard operation level.

(The staff of Hanshou County Bureau gives publicity to retailers)

"Grandma Liu, you are going to be demolished here. I have prepared some materials to facilitate your application!" Xiao Xie, a monopoly worker of the county bureau, walked into Grandma Liu’s shop and said enthusiastically.

Hanshou County Bureau earnestly implements the responsibility system of "whoever enforces the law will popularize it", integrates the popularization of law into market inspection and daily visits, turns static popularization of law into dynamic popularization of law, and turns the law on paper into a sensible law. The county bureau integrates law enforcement with service, and inspectors and city managers walk into cigarette retailers’ shops to carry out face-to-face publicity and one-on-one explanation on the legal issues involved in the standardized operation of retailers, so as to popularize the law in real time and accurately. To explain the case, publicize the tobacco monopoly law and its implementation regulations, help retailers to calculate the "legal account" and "economic account", warn retailers with real cases in their jurisdictions, and advise retailers to operate in good faith and abide by the law, and not to sell cigarettes and e-cigarettes to minors. Using online forms such as WeChat group and Tencent conference live class, the common illegal acts of tobacco monopoly law are interpreted for retailers in easy-to-understand language, so that retailers can understand the law and know awe, keep the "high-voltage line" of standardized cigarette operation, enhance the pertinence and effectiveness of law popularization, and maintain the market order of standardized cigarette operation.

Popularize law into campus and care for students’ healthy growth

(Hanshou County Bureau staff carry out activities of popularizing law into campus)

Hanshou Tobacco Monopoly Bureau strengthens the propaganda of tobacco hazards, makes great efforts to build a smoke-free campus environment, and forms the joint efforts of the whole society to protect the healthy growth of minors. Union County Education Bureau and Market Supervision Administration went into primary and secondary schools to carry out legal publicity activities with the theme of "protecting the future with children". By playing warning videos and explaining in kind, the staff preached to primary and secondary school students the dangers of traditional tobacco products, e-cigarettes and new illegal e-cigarettes such as "milk tea cups" and "coke cans", and resolutely resisted the temptation of tobacco. Combined with the recent popular "cigarette card" game among primary school students, the potential harm of "cigarette card" is emphasized, and students are warned not to be curious, not to follow the trend, not to be contaminated with tobacco, to stay away from Internet cafes, bars, KTV and other entertainment places that are not suitable for minors to enter, and to resolutely say "no" to cigarettes, e-cigarettes, etc. Widely publicize and publish the telephone number of complaints about selling cigarettes to minors, encourage teachers and students to actively report relevant information clues, and guide all sectors of society to protect the physical and mental health of minors.

In the next step, Hanshou County Bureau will normalize, institutionalize and carry out long-term publicity of law popularization, promote the effectiveness of the eighth five-year plan, and hand over socially satisfactory answers.

(Image courtesy of Cao Libin Guan)

The above contents are promotional information, and the contents involved do not represent the views of this website, and do not constitute investment suggestions or consumption suggestions.

The fresh news morning call is all in the morning paper.

In the past two days, the news of Stephen Chow’s new film "killing" was overwhelming, which surprised the younger sister. The news of Crystal and Bo Huang singing for the film swept through again ~ What big things did they do? The new material in the film circle and the expected girl get together to solve it ~

Preview to see Crystal’s voice goddess turn into Spider-Man.

Spider-Man: Into the Spider-Verse, a superhero animated film jointly produced by Marvel Comics and Sony, is believed to be a must-see film that many people want to see. The film will make the concept of parallel universe in Spider-Man series film and television, and gather six Spider-Man in parallel space to resist evil forces together. Among them, the female Spider-Man Gwen Stacy is particularly eye-catching, and her China dubbing is "the goddess of change" Crystal ~

This is Crystal’s first animated film dubbing work. Her cheerful and independent personality coincides with that of the female Spider-Man in the original work. It is said that in order to better perform this role, Crystal, who is not a professional, has developed the habit of reading a poem every night before going to bed, so as to improve her lines. Everything comes to him who waits, Crystal’s final effect is amazing, which makes people exclaim, "Yes! She is Gwen! " If you want to better "identify" Crystal’s dubbing skills, don’t go to the cinema to support it ~

What about the star? Bo Huang is singing again! Sing the theme song for the documentary for the first time

Recently ~, some girls feel that there are many melons to eat, and the entertainment circle is not peaceful! Emmm~ What I’m going to talk about next is a hot spot worth mentioning, as all the fat friends who are concerned about Bo Huang must know, that is, Bo Huang sang the theme song for the documentary for the first time! Some girls watched the MV for the first time, and Bo Huang sang so beautifully! "It’s a little cold this winter. May this song give you some warmth and courage." Yes, everyone who has seen it will feel something! "The stones of life sometimes hurt your feet, so count how much pride there is in the wound." The lyrics in the theme song, through Bo Huang’s warm singing, become both story-telling and powerful.

Documentary film is the third documentary film directed by Han Xiao. This time, director Han Xiao focused on the ordinary little people whose fate and craft are intertwined. The film tells the life story and life choices faced by Huang Zhongjian, a young man who studied Cai Lifo Boxing in Foshan and was obsessed with lion dancing, and Aht, the old man who made a saddle in Xinjiang Kazak. The film will be released nationwide on December 1, 2018. Director Han Xiao said, "It is a very lucky thing for us to be invited to Bo Huang. At first, our team was very uneasy when communicating. After all, this is a very small movie. But what moved us particularly was that Bo Huang agreed to sing for our film after watching our 4-minute trailer. " Touched and voiced for ordinary people, and praised Bo Huang!

Overseas telescope "classic return" special transformers return to the original generation

The action sci-fi movie "Bumblebee" has wonderful flowers and clips! The first rumored film in this series, created by American Paramount Film Company, released a special production of "Classic Return" yesterday. The director Taravis Knight, starring hailee steinfeld, john cena and the behind-the-scenes creator shared their unforgettable memories when they first saw Transformers, and also introduced the design concept of Transformers in the movie "Bumblebee" — — Return to the original classic style.

Director Taravis Knight has always been a big fan of Transformers, and he also praised the film for highly restoring the G1 image, saying that it brought him back to the time when he first fell in love with Transformers. I believe that as soon as this special edition is exposed, the old TF fans will fly in place! Full of G1 animation style, square brother Optimus Prime ~ The film will be released in North America on December 21st. Now, let’s pay tribute to the classic era of autobots with the expected girl and ignite the deep memories!

Industry Broadcast "Cairo China Film Night" Film Festival opens in Egypt and four China films are shown.

At the invitation of the 40th Cairo International Film Festival, the 3-day "Cairo China Film Night" film exhibition kicked off in Cairo on 26th, and four outstanding contemporary China films will be shown, among which "Dong Song" is the opening film of this film exhibition ~

The film exhibition, sponsored by the Chinese Film Association, aims to make more Egyptian audiences and filmmakers know and like China films, and then know and like China better. I believe that this exchange and cooperation between China and Egypt in the field of film will certainly make positive contributions to enhancing understanding between nations and deepening friendship between countries ~

The movie Calendar was born in Lin Chi-ling.

(The specific broadcast content is subject to TV)

Want to get more fresh movie information, love beans, exclusive live video, don’t hurry to download CCTV6 movie channel app, there are girls waiting for you!

1905 movie network news People are never short of police comrades who "cut the demon and get rid of the demon" all the way like "Monkey King". Song Rukun, the Weifang Public Security Bureau, has been fighting in the front line of criminal investigation to crack down on serious violent crimes since he joined the company in 1997. He has participated in the organization and detection of more than 220 serious criminal cases and arrested more than 2,000 criminal suspects in various criminal cases, playing an indispensable and key role in detecting a series of serious and serious cases such as intentional homicide, kidnapping and robbery.

There is also such a "Sun Dasheng" in a movie to be released on December 21st. In the trailer of the "Demon-slaying and Demonizing" version, Sun Dasheng, a criminal justice policeman played by Wang Qianyuan, took the "the Monkey King" key chain in his hand and comforted the children whose father was bullied by evil forces in the canteen: "Uncle, it’s the police who specialize in catching bad guys." The next part of the trailer shows standing up for justice,

Sun Dasheng, who "killed the demon" all the way: In the old garage, facing the vicious gangsters with sticks, Sun Dasheng responded tactfully, flew over the car to avoid pursuit and fought fiercely with the gangsters; On the rooftop, on the way to hunt down Zhao Tai, a sinister rich second generation played by Bao Beier, he was violently blocked by Zhao Tai’s bodyguards, and Sun Dasheng mercilessly grabbed the gangster’s head and gave him a beating; In the square, Zhao Tai had no way to escape, but still insisted on resisting arrest. Sun Dasheng stepped forward to fight for his life, and he must carry out the "demon-cutting and demon-removing" to the end!

Those powerful "monsters" are not "big shots", but "big shots" should be those police comrades who "cut off demons and get rid of demons" all the way. It is precisely because these people’s policemen like Sun Dasheng fight to the end for justice and evil forces that people can enjoy a peaceful and harmonious life with peace of mind. I also hope that the police uncles can protect themselves and pay tribute to the people’s police in the process of eliminating evils!

　　On the afternoon of March 30th, the 2022 excellent network audiovisual works selected by the State Administration of Radio and Television were announced at the 10th China Network Audiovisual Conference. As a comprehensive selection activity for the whole industry, the "National Excellent Network Audio-visual Works Selection Activity" aims to play a leading role in demonstrating excellent network audio-visual works, better meet the new expectations of the people for a better audio-visual life, and gather together the majestic power of struggling for a new era and forging ahead in a new journey.

　　中央广播电视总台央视网共10部作品入选，分别是特别节目《最高领袖与乡村振兴的故事》；网络综艺节目《中央广播电视总台2022网络春晚》；短视频《最高领袖擘画的现代版“富春山居图”》《家风世泽长》《跟着习主席看世界｜最高领袖“典”亮命运共同体》《2021年版清明上河图 藏了一年的彩蛋》《熊猫终极治愈行为大赏》《以梦为马》《好久不见！沉浸式重温70、80、90回不去的童年》;网络直播节目《“中国比利时两国共庆旅比大熊猫双胞胎三岁生日”主题直播》。

特别节目

《最高领袖与乡村振兴的故事》

　　党的二十大召开前夕，乡村振兴战略实施五周年之际，央视网策划推出系列时政微纪录片《最高领袖与乡村振兴的故事》(全5期)，以“山、河、湖、海”作题眼，立足中国版图，围绕最高领袖跨越山海、关心农业农村发展的足迹，展现新时代乡村振兴战略实践成果。尤其《在希望的田野上》一集，采用一镜到底的创意表达，带领观众展开一场穿越之旅，打开振兴之门，看见希望的田野。

Network variety show

CCTV 2022 Network Spring Festival Gala

　　With the theme of "youth is just right, when it is new", the 2022 Internet Spring Festival Evening at the reception desk vividly shows the youthful style and struggle story of the "net-born generation" with the expression of networking and youthfulness, and gathers youthful strength. The party will be broadcast simultaneously through CCTV-1 integrated channel and new media matrix of CCTV, CCTV news, CCTV video, CCTV finance, CCTV literature and art, etc., to achieve cross-circle communication effect.

　　The number of TV viewers reached 143 million, the number of live broadcasts of related content and new media matrix was 150 million, and the number of video broadcasts was 1 billion. It triggered 260 hot topics in the whole network, including 151 hot searches in Weibo.

short video

The modern version of "Fuchun Shan Jutu" painted by the Supreme Leader.

　　General Secretary of the Supreme Leader used the modern version of "Fuchun Shan Jutu" as a metaphor to describe the beautiful vision of rural revitalization in the new era. Based on Fuchun Shan Jutu, CCTV copied and innovated, drew a 6-meter long scroll of traditional Chinese painting, and launched a heavy micro-video, showing the rural butterfly changes under the guidance of the Supreme Leader’s New Era Socialism with Chinese characteristics Thought.

Family style is long.

　　Deze has a long history and a long family tradition. General Secretary of the Supreme Leader emphasized that "family is the first classroom in life, and parents are the first teachers of children". Xi’s family style, adhering to "keeping the family in order" and then "governing the country", comes down in one continuous line and is dedicated to the people. CCTV plans to launch "Family Style and Prosperity" and feel the general secretary’s fiery national conditions.

《跟着习主席看世界｜最高领袖“典”亮命运共同体》

　　2013年，最高领袖主席首次提出人类命运共同体的理念。如今，该理念已成为引领人类文明进步潮流的旗帜。央视网推出微视频，通过VR绘画，带领网友品读习主席阐释命运共同体理念时引用的典故，感悟其中蕴含的中国智慧。

《2021年版清明上河图藏了一年的彩蛋》

　　该片将2021年众多瞬间和元素以彩蛋的形式藏在全图，彩蛋包括人物形象、声音素材、关键物件等，据统计超过200个。彩蛋元素从二次元到三次元，从游戏、动漫、电影、热梗到时政新闻均有涵盖，正如网友评论这是最用心最贴近当代年轻人的一版年终盘点。

《熊猫终极治愈行为大赏》

　　2022年10月27日国际大熊猫日，央视网推出混剪短视频《熊猫终极治愈行为大赏》，记录整合萌宠界各大“顶流”熊猫高萌瞬间，画面更具喜感和萌感，广受海内外网友的喜爱。

《以梦为马》

　　香港回归25周年之际，央视网推出原创动画《以梦为马》，通过举世闻名的“人骑图”和“狮子玉”两匹马从北京南下香港的一路见闻，轻松幽默传播中华传统文化，进而增强文化自信，增进民族认同感。

The miniature scene freeze-frame short film | Long time no see!Immerse yourself in reliving the childhood that you can’t go back to in 70, 80 and 90.

　　The so-called growing up is a journey with no return. In order to welcome the arrival of Children’s Day in 2022, CCTV and the post-1995 miniature landscape creators spent two months recreating the childhood scenes of three generations with a scale of 1:20, and launched a creative miniature scene stop-motion short film "Long time no see! Immerse yourself in reliving the childhood that you can’t go back in 70, 80 and 90.

Webcast program

"China and Belgium celebrate the third birthday of the giant panda twins".

　　On the occasion of the 51st anniversary of the establishment of diplomatic relations between China and Belgium, CCTV Panda Channel, together with many authoritative organizations, launched the world’s first live broadcast of the theme of "China and Belgium celebrate the third birthday of the giant panda twins", and the overseas connection for the celebration of the giant panda’s birthday caused a topical discussion, which set a new high in the live broadcast effect of the overseas account of Panda Channel in 2022. This live link between China and Belgium shows a colorful and vivid image of China, and promotes cultural and cultural exchanges between China and Belgium.

　　Guided by the spirit of the 20th National Congress of the Communist Party of China, CCTV, the General Station of Central Radio and Television, will always take innovation as the main theme, vigorously promote the integrated communication of "thought+art+technology", and strive to create more excellent network audio-visual works with both positive energy and large flow, serving the country’s governance, a better life and economic and social development.

　　Recently, the General Office of the Guangdong Provincial Committee of the Communist Party of China and the General Office of the Guangdong Provincial People’s Government issued the Notice on Doing a Good Job during the Spring Festival of New Year’s Day in 2024, requiring all localities and departments to conscientiously implement it. The full text is as follows.

　　The year 2024 is the 75th anniversary of the founding of People’s Republic of China (PRC), so it is very important to do all the work well during New Year’s Day and Spring Festival. All localities and departments in the province should adhere to the guidance of Socialism with Chinese characteristics Thought of the Supreme Leader in the New Era, fully implement the spirit of the 20th National Congress of the Communist Party of China and the Second Plenary Session of the 20th Central Committee, conscientiously implement the requirements of the Notice of the General Office of the General Office of the Central Committee of the CPC and the State Council on Doing a Good Job during the Spring Festival of New Year’s Day in 2024, implement the "1310" specific deployment of the provincial party committee, and earnestly do a good job in the work during the festival from the political height of adhering to the "two establishment" and "two maintenance" to ensure that the people spend a happy and peaceful time.

　　First, increase assistance and care for people in need.Hold fast to the bottom line of basic livelihood security, and pay basic pension, unemployment insurance, subsistence allowance, destitute support and basic living allowance for orphans (in fact, there is no one to raise children) on time and in full. Where conditions permit, the relief funds during the "two festivals" can be paid in advance or a one-time living allowance can be added. We will do a good job in helping the needy people in send warm, increase visits, condolences and assistance to the homeless and beggars, the disabled, all kinds of children in distress and other special hardship groups, strive to solve the production and life problems of the urban and rural needy people, and send the care and warmth of the party and the government to the hearts of the needy people. In-depth visits to party member, old party member, veteran cadres and retired military cadres, Red Army veterans, old demobilized soldiers, disabled soldiers, families of martyrs, etc. Solidly carry out the special campaign to eradicate wage arrears in winter, strengthen the classification, verification and disposal of clues reflecting the platform problems of the national wage arrears, and quickly check and settle the discovered wage arrears clues to protect the legitimate rights and interests of migrant workers. All localities should strictly implement the assistance system for families living on the edge of subsistence allowances and families with expenditure difficulties, strengthen active discovery, monitoring and early warning, promptly accept and respond to people in need for help, and do urgent things for the newly verified minimum living allowances, increase the intensity of temporary assistance, and timely solve the sudden and urgent basic living difficulties encountered by urban and rural people.

　　Second, strengthen market price stability and supply to meet holiday consumption demand.Strengthen the protection of important living materials, strengthen the dynamic monitoring of the supply and demand of coal, electricity, oil and gas transportation, scientifically dispatch resources, enhance the peak power generation capacity, and compact the main responsibility and territorial responsibility of the enterprise to ensure the stability of power supply and gas supply. We will implement the responsibility of the party and government for food security and the mayor’s responsibility system of "vegetable basket", do a good job in ensuring the supply and price stability of important livelihood commodities such as grain, oil, meat, eggs, milk, fruits and vegetables, strengthen the connection between production and marketing, inventory scheduling and logistics distribution, and ensure that the supply of daily necessities is not out of stock. Formulate emergency supply plans for daily necessities, closely track daily supply and prices, strengthen market price inspections on holidays, and increase reserves in a timely manner. Standardize the market order of cultural tourism holidays, strengthen price supervision in key areas of people’s livelihood such as catering accommodation, scenic spot tickets and parking fees, and promptly investigate and deal with illegal acts such as price gouging, price collusion and price fraud. Standardize promotional activities, urge online trading platforms to implement the main responsibility, strengthen online trading and service supervision, and safeguard the legitimate rights and interests of consumers. Strictly implement the "four strictest" requirements of food safety, continue to promote the work of fasting wild animals, and ensure "safety on the tip of the tongue".

　　Third, enrich the spiritual and cultural life of the masses and actively create a festive atmosphere.Focusing on the full implementation of the spirit of the 20th National Congress of the Communist Party of China and the Second Plenary Session of the 20th Central Committee, we will strengthen publicity and guidance with strong confidence as the focus, organize various cultural and artistic activities with rich connotations, arouse the enthusiasm of the broad masses for loving the Party, the motherland and socialism, consolidate and expand the mainstream ideological public opinion in the new era, carry forward the main theme, and gather the powerful forces of unity and forge ahead of the whole society. Do a good job in the free opening and service of public cultural places such as libraries, cultural centers, museums and art galleries. Vigorously carry forward the socialist core values and Chinese excellent traditional culture, eulogize the new era, and constantly meet the spiritual and cultural needs of the people.

　　Four, do a good job in Spring Festival travel rush security, to ensure the safe and orderly travel of the masses.Make a service guarantee work plan for Spring Festival travel rush as soon as possible, and do a good job in Spring Festival travel rush. Analyze and judge the changing trend of passenger and freight flow, strengthen the propaganda and guidance of off-peak travel, and optimize the transportation capacity for key periods such as college students’ school holidays and migrant workers’ return to their hometowns, as well as key areas such as passenger hubs, railway stations, port passenger stations, airports and tourist attractions, so as to improve the passenger collection and distribution capacity. Cooperate to promote cross-transport mode cohesion organizations, strengthen the overall arrangement of different modes of transport such as roads, railways, civil aviation and waterways, strengthen coordination and cooperation between intercity transport and urban public transport, improve coordination and liaison mechanisms, broaden information exchange channels, and promote open sharing of resources. Strengthen the operation and management of expressway service areas, improve the quality of services such as charging, dining and going to the toilet, strictly implement the policy of free passage of minibuses during the Spring Festival holiday, further sort out easy-to-block sections and expressway toll stations, and implement anti-blocking measures in advance. Strengthen road network operation monitoring, optimize dispatching management, strengthen on-site duty, and strengthen on-site guidance and special handling. Strengthen the smooth transportation and logistics, and ensure that the transportation services of important materials such as energy, food and medical care are not interrupted. Carefully formulate emergency plans to deal with emergencies, actively guard against the surge in passenger flow, freezing rain and snow, etc., strengthen inspection and control of key sections in mountainous areas of northern Guangdong, Qiongzhou Strait, inland river routes, etc., and do a good job in emergency rescue preparations and emergency material support. Strengthen departmental cooperation and regional joint law enforcement, severely crack down on acts such as overloading and speeding, illegal operation, illegal manned vehicles and trucks, and prevent serious traffic accidents.Ensure the safety of people’s travel.

　　Fifth, strengthen the investigation and rectification of potential risks and resolutely hold the safety bottom line.Adhere to the people first, life first, strictly implement the safety production responsibility and management system, pay close attention to various control measures, strengthen the investigation and rectification of key safety hazards, compact the main responsibility of enterprises, and resolutely curb the occurrence of serious accidents. Pay close attention to safety precautions in key industries, strengthen safety supervision of special equipment, construction, dangerous chemicals, non-coal mines, metal smelting, town gas, fireworks and firecrackers, fishing vessels, offshore wind power, religious places, and solidly carry out special actions on fire prevention in winter and spring for large-scale complexes, high-rise buildings, restaurants, "three small" places, and self-built commercial houses. Strengthen the deployment of low-temperature freezing safety precautions, encrypt meteorological monitoring and forecasting, and release early warning and forecasting information such as extreme weather, freezing frost and road icing. Strengthen the safety improvement of all dangerous operation links of dangerous projects, as well as limited space, temporary electricity consumption, cross-fire and other operations. Strictly prevent and strictly control forest fire risks, fully implement the work measures of "covering the mountain, guarding the intersection, focusing on key points, signing responsibilities, and fighting early and small", strictly control the fire sources such as returning home people entering the mountains to sacrifice graves, setting off fireworks and firecrackers, and burning in the wild to warm up, strengthen mountain patrol and forest protection, and improve the ability of monitoring and extinguishing. Closely combined with the characteristics of social security at the end of the year and the beginning of the year, we will severely crack down on "pornography, gambling and drugs", "robbery and fraud" and prominent illegal crimes in the fields of telecommunication network fraud, black and evil, food and drug environment, and strictly examine and approve large-scale activities such as New Year’s Eve, fireworks parties and temple fairs, and monitor the flow of people, so as to prevent major public safety incidents and earnestly safeguard the overall harmony and stability of society.

　　Six, strengthen the prevention and control measures of infectious diseases, and effectively protect the health of the people.Coordinate the prevention and control of respiratory infectious diseases such as COVID-19 and influenza, increase the overall planning of medical resources, enrich the medical strength of key departments such as outpatient, emergency, pediatric, respiratory and severe diseases in medical institutions, strengthen the preparations for commonly used drugs, testing reagents, medical equipment and beds in medical institutions, optimize the diagnosis and treatment process, shorten the waiting time and reduce cross-infection. Continue to strengthen the monitoring of the diagnosis and treatment of respiratory diseases and the judgment of the situation, do a good job in epidemic monitoring, early warning and risk assessment, strengthen epidemic reporting, and release information in a timely manner. Scientifically publicize the knowledge of prevention and treatment of acute respiratory infectious diseases, continue to strengthen vaccination work, and advocate people to wear masks, do personal protection and maintain good hygiene habits.

　　Seven, advocate thrift and civilized holidays, adhere to the rectification of the "four winds".Persevere in implementing the spirit of the eight central regulations and their implementation rules, grasp the changes and trends of the "four winds" during the holiday season, strictly investigate the problems of illegal eating and drinking, illegal receiving and delivering gifts and gifts, illegal use of buses, public travel, etc., vigorously rectify the phenomena of high-end tobacco, alcohol, tea, "luxury New Year’s Eve", excessive packaging of festivals and gifts, and invisible variation behaviors such as express gift giving, receiving and delivering electronic red-envelope, "not eating public money to eat the boss" and using private cars for public support, and severely punish outstanding subsidies and subsidies. Keep a close eye on the formalism and bureaucracy that increase the burden on the grassroots, resolutely correct and punish the random assignment of tasks to the grassroots in the name of summing up and promoting the work, and set up video conferences with the same theme at different levels. Many people repeatedly ask for materials and fill out forms, supervise and check too much, leave too many marks, and engage in "formalism at the fingertips". Vigorously correct the problems of inaction and chaos in people’s livelihood security, assistance and relief, and safety in production, and promote the solution of the people’s urgent problems. Adhere to and carry forward the fine traditional style of the Chinese nation, solidly promote the change of customs and traditions, strictly educate family members, oppose bad habits such as ostentation and extravagance, showing off wealth by comparison, extravagance and waste, and advocate good social customs. Strengthen pre-warning, in-process supervision, and after-the-fact investigation, increase the investigation and exposure of violations against the wind, and create a festive atmosphere.

　　Eight, do a solid job on duty, to ensure the orderly operation of all work.Strictly implement the system of 24-hour special personnel on duty and leading cadres taking classes on the job and going out to report. Strictly implement the system of asking for instructions and reporting, and in case of sensitive incidents, serious emergencies or other important emergencies, ask for instructions and report at the first time and properly dispose of them in time. Emergency rescue teams should always be in an emergency state and preset rescue forces in advance to ensure timely and effective handling of emergencies. Units that directly serve the masses should reasonably arrange duty during the festival to ensure the quality of service. Strengthen the judgment of government affairs in public opinion monitoring, be good at capturing "weak signals" and strengthen information submission.

　　All localities and departments should improve their political positions, strengthen their organization and leadership, carefully and orderly do all the work during the Spring Festival on New Year’s Day, and ensure that the central decision-making arrangements and the implementation of the spirit of this notice are in place.

In March 2021, when the financing was announced, media reports showed that there were more than 1 million riders in the flash.

Just over three years later, the flash prospectus shows that there are 2.7 million registered riders, an increase of nearly 1.7 million.

However, during this period, the revenue of flash delivery only increased by about 50%, far less than the growth rate of riders.

The result can only be the compression of delivery time and the decline of revenue per order.

Just needed, small track

Express delivery, logistics, take-out and instant delivery are essentially the exchange of money and time. It takes some people’s time to help others complete time-consuming and labor-intensive things.

Express delivery and logistics are long-distance delivery, take-out is short-distance delivery, and running errands and the same city are in between. Flash is located on this track. Because Dada occupied the "first share of instant retail" and SF City became the "first share of third-party instant delivery", Flash delivery had no chance to become the "first share", so it was necessary to emphasize its uniqueness, so it became the "largest independent on-demand delivery service provider".

The so-called on-demand courier service is one-to-one express delivery, and the flasher only serves one customer at a time from picking up to delivery, and delivers it point to point. In this mode, flash has several core advantages.

First of all, one-to-one service, each important document has a direct person in charge, and there are almost no problems such as lost parts and damage. The flash prospectus shows that in 2023 and the first half of this year, its loss rate is very low, only 0.01%.

Secondly, compared with other distribution, one-to-one service naturally costs more. According to the prospectus, customers are willing to pay a high price for the service experience. According to iResearch, the average price per order in the first half of the year was 16.5 yuan, which is a significant premium compared with other major participants in the on-demand distribution industry.

Third, just need. In the case of safety requirements, one-to-one distribution is naturally more secure than centralized distribution, especially for items with strong timeliness and great importance. For first-tier cities, although such scenes do not often appear in work and life, most people will have demand more or less.

The story of "saving" the marriage between Justin and Zhang Xinyi is often mentioned. In 2016, Zhang Xinyi and Justin will hold a wedding in Germany. At the airport, because Zhang Xinyi forgot to bring his mobile phone and wedding veil, thanks to the timely delivery of the younger brother, the trip was not delayed. This aspect reflects the value of instant delivery.

According to the prospectus, on this track, flash has occupied 33.9% market share. However, this is not a big track. In 2023, the revenue of flash delivery was 4.5 billion. From this calculation, the whole market was only 13.2 billion, and it was a small track with a very obvious ceiling.

Focus is the key to the success of flash.

The flash startup team lacks "star flavor". Founder Xue Peng graduated from the School of Science of North China University of Science and Technology in 2005, majoring in information and computing science, and then went to the Royal holloway College of University of London to study for a master’s degree. He has very little information. It is reported that his family conditions are good, and his family involves many enterprises such as real estate, taxis and driving schools, but this low-key "rich second generation" finally chose to start a business. In 2007, Xue Peng returned to China to start a business and founded an integrated service platform for express logistics-Easy Post.

In contrast, Kuai Jiaqi, founder of Dada Group, graduated from Massachusetts Institute of Technology. He holds a bachelor’s degree in logistics engineering from Tongji University and a master’s degree in logistics engineering from Massachusetts Institute of Technology.

However, Flash finally broke through in the fierce competition and once became the "leader" of the industry. It has successively completed 11 rounds of financing, attracting many well-known investment institutions such as Lei Junshun Capital and Jingwei Venture Capital, and Pusi Capital, a subsidiary of Wang Sicong, has also participated in the investment for two consecutive rounds.

Listing is capital.

Flash delivery has always been the main on-demand mail service, and today, it still maintains a good development situation.

According to Xue Peng’s understanding, once the city-wide real-time distribution mode from person to person forms a scale, it will form a strong competitive advantage and the entry threshold is relatively high. Flash delivery has indeed built a certain industry barrier for itself. For example, there are 2.7 million registered riders, 88.9 million users, more than 270 million orders a year, and higher customer unit prices in the industry. In terms of rider and user scale, brand awareness, customer consumption willingness, etc., flash delivery does have a good accumulation.

In terms of performance, the development of flash delivery is in good condition. The overall order volume of flash delivery keeps increasing. The orders in 2021-2023 and the first half of 2024 were 159 million, 213 million, 271 million and 138 million respectively. With the increase of orders, the revenue also keeps growing, which is 3 billion yuan, 4 billion yuan, 4.5 billion yuan and 2.3 billion yuan respectively. Under normal circumstances, it is highly probable that this year’s growth will continue to be positive, but the growth rate continues to slow down.

Flash also maintained a stable profit. In 2023, the profit was 110 million, and in the first half of this year, the profit was 120 million, which had the effect of government subsidies, but it was still profitable if this factor was excluded. In contrast, Dada Group has never made a profit, losing 600 million yuan in the first half of this year.

Cash flow has also steadily turned positive in the last year and a half. The inflow was 45.71 million yuan in 2023 and 20.67 million yuan in the first half of this year. Cash increased from 690 million in the same period last year to 710 million in the middle of this year, which has increased steadily in recent years.

As early as 2020, Flash executives said in an interview with the media that the company may go public soon. At that time, Flash was in a state of loss, and perhaps it really needed listing financing, but the financing was received in the following year, and it was profitable again in 2023. Flash has entered a relatively positive track, and the urgency of the company’s listing financing is not strong, more like listing to meet the requirements of the capital side.

In mid-2020, Dada Group became the first share of instant delivery. After more than four years, its share price has shrunk by 90%. At the end of 2021, SF Express, an independent company, went public in Hong Kong, and its share price was slightly better, shrinking by 30%.

With the previous reference, Flash was broken on the second day of listing and once fell to $11.47, which was not sought after by the market.

The problems faced by flash at this stage make the future more unknown.

Struggling 2.7 million riders

Focus is the key to the listing of Flash, but it is also the reason why Flash can’t open the situation.

There are few companies that don’t make any kind of distinction between revenues, and flash delivery is one of them. A single business is closely bound to the order volume, and the revenue will increase when the order volume is high. After 10 years of development, the on-demand courier service has entered a gentle development period, which is also the reason why there has been no financing for flash delivery in the last three years. If you want to increase orders, you need to reduce prices and expand the market.

According to the order volume and revenue, the average revenue per order in 2021-2023 and the first half of 2024 was 19.12 yuan, 18.79 yuan, 16.71 yuan and 16.55 yuan respectively. In a state of continuous decline.

In addition to price reduction, flash delivery is also increasing consumption scenarios. At first, the main scenes were urgent matters, important documents, etc. Later, Flash began to provide expedited delivery services for customers of local restaurants, flower shops and bakeries, and to distribute valuable electronic products to consumers.

The expansion of the scene will indeed increase the order volume, but as mentioned above, the space in this market is too small. Instant delivery can be divided into four categories, namely, food and beverage takeout represented by Meituan and Hungry, which is high frequency, strong demand and most valuable. Fresh home delivery and Shangchao, represented by Dada, are equally high-frequency and just needed, but to a lesser extent than takeout. The logistics in the same city, represented by SF Express, is not high-frequency, but it faces more scenes and has stronger carrying capacity. Finally, there is the running errands represented by flash, and the demand frequency is lower than other modes.

Without the high-frequency feature, flash can’t use full-time riders like Meituan and Hungry, so it can only adopt crowdsourcing mode. Therefore, there are a large number of riders, with 2.7 million riders far exceeding 1.2 million in Dada Group and 950,000 in Shunfeng City, almost reaching the scale of being hungry. But obviously, the presence of the flash rider is far lower than that of hungry.

The advantage of flash delivery is that the customer unit price is high, and there is a lot of room for operation. However, crowdsourcing riders are not loyal, and they often take orders from multiple platforms at the same time, resulting in high personnel mobility. This requires flash delivery to benefit riders as much as possible. In 2021-2022, the salary and reward paid by flash delivery will exceed 90.5% of the revenue. However, the flashing needs to be profitable, and it has to be directed at the rider. In 2023 and the first half of this year, the proportion dropped to 85.4%.

To sum up, on the one hand, it is necessary to reduce the price and increase the order, on the other hand, it is necessary to maintain a high share for the rider, and on the other hand, it is necessary to consider its own operation and reduce the cost from the rider as much as possible. According to the scale of 2.7 million riders, combined with revenue, order volume and unit price, in 2023, there will be 740,000 orders per day, generating revenue of 12.41 million yuan, and the reward allocated to riders will be 10.9 million yuan. By this year, although there are 770,000 orders every day, the reward allocated to riders is only 10.84 million, with the increase of orders and the decrease of rewards.

At the same time, the prospectus shows that in 2021-2023 and the first half of this year, the average delivery time of orders was 35 minutes, 31 minutes, 29 minutes and 27 minutes respectively, which has been compressed, and the delivery pressure of riders continues to increase.

The rider’s income drops, the pressure of order limitation continues to increase, the competition becomes cruel, and the living environment is very difficult. At the present stage, it is no problem for riders to increase their income sources, but after all, they can’t keep the platform running by squeezing riders.

Of course, rider ecology is not a serious problem, and the real challenge comes from the external environment.

Small and beautiful, false proposition

Without backing the giants, the most well-known employer is Shunwei Capital of Xiaomi, accounting for only 7.8% of the shares. Although it is known as the largest on-demand delivery service platform, the scale of flash delivery is only half that of Dada and less than 40% of that of SF. Such a "small but beautiful" platform is often difficult to maintain for a long time in China Internet market.

The so-called moat flashing is more relative to the start-up platform. At this stage, it is not a small platform that competes with flash. Meituan’s errands, hummingbirds, SF Express and Dada are all backed by super platforms, and the order volume is incomparable. These platforms are involved in the field of flash, which is just a supplement to the business. Taking SF City as an example, getting involved in the same city business is only to supplement the short-distance delivery business and improve the choice of customer unit price, which can increase the income of the courier brother, and also expand the fresh home delivery, Shangchao and even take-away business when necessary, and improve the human efficiency without harm.

Giants not only have traffic, brands, service guarantees, but also the ability to price war. Previously, SF executives in the same city mentioned that the price is expected to fall this year, and the price is its core competitiveness. There is no doubt that in the face of price war, flash has basically no ability to parry. Flash delivery has almost no counter-ability, and it can be said that it is difficult for flash delivery to enter the take-away and logistics markets.

In fact, flash delivery is in a state of being a fish. In 2021, after the D2 round of financing, the flash valuation reached 2 billion US dollars. In 2024, the Hurun Global Unicorn List, the flash valuation was 7.1 billion yuan. After listing, the market value of Flash is only $1.07 billion. The downward adjustment of the flash valuation in the capital market has already explained many problems.

Flash delivery is actually a microcosm of the economic development of the Internet platform. Small and beautiful is a false proposition. If the scale is not reached, it will be impossible to compete with the giants. We can only pray that the giants will despise the "fly legs". An action of a giant that is often completely irrelevant may directly determine the life and death of a platform.

References:

1. A single income in 16 yuan, 2.7 million riders sent to the market, source: fixed focus.

2. Before going to the US IPO, flash to deal with the "same paragraph" problem of SF. Source: Wall Street.

3. Flash IPO to the United States: the price of a single customer has been declining year after year, and the unicorn valuation is "big waist" | BUG, source: Sina Technology

　　On August 9th, as a sub-activity of the 6th Global cross-border electronic commerce Conference, the first global cross-border e-commerce youth innovation and development summit forum was held in Zhengzhou E Trade Expo Center.

　　More than 300 people from international organizations, heads of well-known logistics enterprises at home and abroad, young talent leaders of cross-border e-commerce, senior youth entrepreneurship and employment guidance experts, and university scholars gathered together to discuss new ideas and ideas for the development of cross-border e-commerce industry in the new era around the theme of "New Economy, Creating Youth and Winning the Future", and share innovative ideas and scientific research achievements such as cross-border e-commerce brands going to sea, trade transformation, and young talent entrepreneurship and employment.

　　Today’s Henan needs a group of outstanding young talents with creativity and high skills more than ever before. "Young people are the main force in the cross-border e-commerce industry. This forum is to build a platform for cooperation and exchange for them, and further lead the young people in the cross-border e-commerce industry to actively participate in the strategy of innovation-driven, rejuvenating the province through science and education, and strengthening the province with talents, and contribute their youth to accelerating the construction of national innovative highlands and institutional open highlands." Hairun Hua, member of Henan Provincial Committee of the Communist Youth League and secretary of Zhengzhou Cross-border E-commerce Industry Working Committee, the initiator of this forum, said.

　　"We must encourage young people in the new era to show their youthful vitality and voice their voices in the practice of joining the cross-border e-commerce industry, and actively provide a good communication platform for young talents to learn cross-border e-commerce knowledge under the new situation and improve their professional skills in the industry." Li Jianwei, executive vice president of the Provincial College Graduates Employment Promotion Association, said.

　　In recent years, cross-border e-commerce in Henan has grown against the trend under the situation of epidemic prevention and control, and provided assistance for global epidemic prevention. The construction of the "Online Silk Road" has been deepening. Lu Shuifu, deputy secretary of the Party Committee of Henan Bonded Group, said that he hopes that this forum can widely mobilize and lead young people to become pioneers of scientific and technological innovation, so that the "youth" power can be deeply integrated with the "youth" industry, and innovation can become an inexhaustible motive force for blooming youth; The group will continue to explore new ways and means to serve young people in the cross-border e-commerce industry, and strive to formulate standards for training young talents in this industry.

　　"In today’s big data environment, many young talents have flooded into the e-commerce industry. The phenomenon of live broadcast in online celebrity has become a social craze, which is a brand-new shopping experience for overseas consumers." Yuan Chunlin, a doctoral tutor at Henan University, said. In his speech, he shared the research results on the formation process, effect and management logic of quasi-social experience in the live broadcast situation in online celebrity.

　　On the same day, Xingyao Yifeng Group signed strategic cooperation contracts with Kaifeng Education and Sports Bureau, Luohe Vocational and Technical College, Kaifeng University and Zhengzhou Vivian Dawson International Textile City on school-enterprise cooperation, youth talent training, and the joint construction of cross-border e-commerce incubation base and e-commerce industrial park. (Reporter Song Min)