Tumor immunotherapy is one of the most promising research directions in the field of tumor therapy, and the preliminary clinical trial results show that its therapeutic efficiency is very high. Classification of tumor immunotherapy According to the chronological order of application of different mechanism therapies, it mainly includes non-specific immune stimulation, immune test point monoclonal antibody, relay cell transfusion, monoclonal T cell receptor therapy, CD47 monoclonal antibody, tumor vaccine, etc. Non-specific immune stimulation: The mechanism of these therapies is to enhance the antigen presentation process by stimulating T cells or antigen presenting cells, in addition to suppressing immunomodulatory T cells that can also enhance T cell activity. These therapies emerged in the 1970s but their use was limited by the length of treatment, toxicity, and limited scope of treatment of tumors. (1) Drugs that enhance antigen presentation by stimulating T cells include: interleukin-2 (IL-2), interferon alpha (IFNα), used in melanoma and kidney cancer. (2) Drugs that enhance antigen presentation by stimulating antigen-presenting cells include: Toll-like receptor ligand imiquimod for the treatment of basal cell carcinoma and BCG (bacterial agent) for local perfusion of bladder cancer. (3) Drugs that enhance antigen presentation by inhibiting immunomodulatory T cells include: CD25 monoclonal antibody that binds to the IL-2 receptor alpha chain of immunomodulatory T cells. Immunosuppressant dalizumab Daclizumab, denibulin-2 for the treatment of cutaneous T-cell leukemia and ovarian cancer, cyclophosphamide for the treatment of tumors and autoimmune diseases. 2, immune test point monoclonal antibodies: At the end of the 20th century with the in-depth study of the antigen presentation process, research has shown that active immunotherapy is the activation of its own immune system T cells or antigen presenting cells to identify and kill tumor cells, the activation of T cells requires two signals: one is the signal of MHC-peptide, the other is the signal of co-stimulatory molecules, mainly positive co-stimulatory factors CD27, CD28 and CD137 pathways. In addition, to ensure that T cells are not overstimulated, there are also costimulatory molecules that regulate T cells from being overstimulated, mainly the CTLA4 pathway and the PD1/PDL1 pathway, which are inhibitory pathways that can also be hijacked by tumors to fight against the immune system. Increased immune killing of tumors can be achieved by combining agonists of positive costimulatory factors, or inhibitors of negative costimulatory factors. The concept of “delayed effect” of immune test point monoclonal antibodies has been proposed by BMS and the academic community due to the fact that some patients may experience remission only after a period of time, and a new criterion for evaluating the efficacy of oncology treatments has been proposed – immune-related efficacy evaluation. Adverse effects related to excessive activation and expansion of T cells can also occur, and clinically observable autoimmune damage can occur in some patients’ organs. The challenge with immune test site monoclonal antibodies is that they only unwind or enhance the presentation of T cells already located at the tumor margin, they do not prompt T cells to attack the tumor, and some patients do not immune respond. 3. Relay cell transfusion: Relay cell therapy (ACT) mainly includes tumor infiltrating lymphocyte therapy (TIL), T cell receptor therapy (TCR) and chimeric antigen receptor-modified T cell therapy (CAR). Among them, TCR and CAR are able to specifically kill various types of tumor cells by recognizing antigen-MHC complexes and antigens, respectively. (1) Tumor infiltrating lymphocyte therapy (TIL): Tumor tissues are removed from the patient’s body, the T cells in them are isolated and expanded by adding IL-2, and then infused back into the body to expand the immune response, mostly in combination with chemotherapy. Effective only in metastatic melanoma (40% long-term remission) because in metastatic melanoma anti-cancer lymphocytes enter the tumor and are therefore easier to isolate, but it is difficult to collect other non-solid tumor anti-tumor T cells from the blood. There are other problems such as the need to culture the cells in vitro resulting in patients having to wait 4-6 weeks to start treatment, the less easy expansion of specific anti-cancer T cells in vitro culture, and the high cost of treatment. (2) T-cell receptor therapy (TCR): Ordinary T cells from the peripheral blood of patients are extracted and new genes are introduced through a viral vector to express TCRs that recognize cancer cell antigens as well as some immune factors, thus activating and directing T cells to seek to kill cancer cells. The advantage is that it can obtain various tumor antigen-specific receptors and thus treat various tumors. The disadvantage is that it will attack normal cells with the same antigen as the tumor, and it is difficult to bind the inserted TCR specifically to the MHC in vivo, resulting in poor actual tumor-specific binding ability. (3) Chimeric antigen receptor-modified T cell therapy (CAR): CAR therapy is similar to TCR therapy in principle, except that the TCR recognizing cancer cells is replaced with an antibody-like antigen receptor, and the components for activating T cells are embedded at the other end of the receptor, and multiple co-stimulatory molecules are introduced into the chimeric protein, which makes the T cells’ viability, proliferation ability and memory effect enhanced, thus activating the guide T cells looking to kill cancer cells. From published small clinical data, some CAR therapies have achieved complete remission rates of up to 60%, and all in patients who were ineffective with other treatments.CAR appears to have no dose effect and is able to produce an amplification effect in vivo, with some reports suggesting that CAR can amplify more than a thousand-fold in vivo, but some ineffective patients may not amplify in vivo due to weakened immune function. The side effect is also to attack normal cells with the same tumor antigen, causing a cytokine storm and producing tumor lysis. Subsequent improvements include finding tumor-specific antigens that are not present in normal cells, adding chimeric co-stimulatory receptors that can bind both antigens to the TCR to reduce damage to normal cells, adding different co-stimulatory factors to act on different tumors, and immune testing point monoclonal antibodies or TCRs in combination, and improving cell culture techniques. 4, monoclonal T-cell receptor therapy: British company Immunocore developed monoclonal T-cell receptor therapy (mTCR), will be able to identify the tumor cell surface and intracellular mTCR with the ability to activate the T-cell anti-CD3 scFv connected together, the patient input this mTCR drug will be able to activate, guide T cells to find and kill cancer cells. The advantage is that no genetically modified T cells are required, no in vitro cell culture is necessary, and a large number of tumor antigens within the cell can be bound compared to monoclonal antibodies. Currently Genentech, GSK and AZ have formed a strategic alliance with Immunocore. 5.CD47 monoclonal antibody-blocking phagocyte “don’t eat me” pathway: CD47 monoclonal antibody enhances the killing effect of phagocytes on tumor by relieving the evasion effect of tumor on phagocytes, and preclinical trials have shown that the combination with tumor-specific monoclonal antibodies is effective. CD47 is widely expressed on the surface of different tissue cells, such as hematopoietic cells (erythrocytes, lymphocytes, platelets, etc.), non-hematopoietic cells (placenta, liver and brain cells, etc.) and tumor cells. Protocarcinoma cells express both calreticulin, which promotes phagocytosis, and CD47, which inhibits phagocytosis, in a dynamic balance; under pathological conditions, CD47 expression increases, inhibiting calreticulin-mediated phagocytosis and allowing tumor cells to escape from immune surveillance. The use of anti-CD47 antibody to inhibit or block the signaling pathway of CD47 would be a very effective new pathway for tumor immunotherapy. Experiments in mouse models have found that anti-CD47 antibodies can reduce the burden of lymphoma and improve the survival rate; if used together with rituximab, they can cure lymphoma. Tumor vaccine: The mechanism of action of tumor vaccine is to stimulate T cells in the body through tumor antigens in the presence of presenting cells, thus “domesticating” them to produce immunocidal effects on tumors, in the form of proteins, peptides, plasmid DNA or viral coding products (viruses also have direct tumorolytic effects), and specific antibodies. Specific antibodies can also be used as vaccines for certain B-cell malignancies. Such vaccines require the addition of adjuvants including colony-stimulating factors or Toll-like receptor ligands. Another approach is to extract antigen-presenting cells from the patient, load them with tumor antigens in the presence of cytokines or adjuvants, and infuse them back into the body. The disadvantage is that such personalized vaccines are complex and expensive to produce with poor long-lasting efficacy.