Tumor escape refers to the phenomenon that tumor cells can survive and proliferate in the body by evading the recognition and attack of the body’s immune system through various mechanisms. When malignant cells appear in the body, the immune system can identify and specifically eliminate these “non-self” cells through immune mechanisms to prevent the development of tumor. However, under certain circumstances, malignant cells can evade the body’s immune surveillance through various mechanisms and proliferate rapidly in the body to form tumors. In other words, on the one hand, the body can resist the occurrence of tumor through natural and acquired immunity; on the other hand, tumor cells can evade the recognition and attack of the body’s immunity through various mechanisms. The occurrence and regression of tumor depends on the overall effect of these two aspects. The in-depth study of tumor immune escape mechanism has provided new ideas to explore tumor immunotherapy. At present, many immunotherapeutic regimens for reversing tumor immune escape are in clinical trials, and a significant portion of them have been applied in the clinic. In this paper, we briefly explain the progress of tumor immune escape mechanism and immunotherapy in recent years. I. Mechanisms of tumor immune escape and new therapeutic ideas A variety of mechanisms are involved in tumor immune escape. Among them, the immune “selection” of immunosurveillance also contributes to the immune escape of tumors. The new view of immunosurveillance theory suggests that the immune system can remove tumor cells that are sensitive to immune response, while tumor cells that are not sensitive to immune response are “selectively” retained and can proliferate rapidly. Therefore, it is believed that immunosurveillance on the one hand also promotes the rapid proliferation of these tumor cells with immune escape ability, and the body’s anti-tumor immunity becomes weaker and weaker. However, the prerequisite for immune “selection” is that tumor cells acquire the ability to resist immune attack and/or suppress the body’s immune response, i.e., acquire the ability to immune escape. Immune tolerance, immunosuppression and immune senescence are the main mechanisms by which tumors acquire immune escape ability. (A) Immunosuppression 1. Secretion of immunosuppressive factors or activation of immunosuppressive cells Studies have found that certain tumor cells can secrete immunosuppressive factors, such as transforming growth factor beta (TGF-β), interleukin-6 (IL-6) and prostaglandin E (PGE2), through autocrine or paracrine forms, which can inhibit the body’s killing of tumor cells. Tumor can induce the body to produce immunosuppressive cells, which play a negative regulatory role on the body’s anti-tumor immune response and is one of the main mechanisms of tumor immune escape. Treg can be either CD4+ T cells or CD8+ T cells, and Treg suppresses the proliferation and activation of effector T cells and suppresses the secretion of helper T cells 1 (Th1). cytokine secretion, thereby suppressing the body’s anti-tumor immune response [2]. In addition, it has been shown that CD4+CD25+CD127(low/-) Treg in gastric cancer patients is associated with tumor stage [3]. However, Salama et al. showed that local infiltration of FOXP3+ Treg in colorectal cancer tissues improved the prognosis of patients in early stages [4]. What has attracted attention in recent years is the widespread presence of bone marrow-derived suppressor cells (MDSCs), including immature macrophages, granulocytes, and DC cells, in the peripheral blood and tumor tissues of tumor patients. These cells are further activated upon arrival in the periphery and can express a variety of pro-angiogenic factors and are capable of suppressing the immune response of T cells and NK cells, which in turn are involved in suppressing the body’s anti-tumor immunity [5]. Inducing the differentiation and maturation of MDSCs and inhibiting the expansion of MDSCs is the idea of tumor immunotherapy targeting MDSCs. Studies have shown that VEGF is one of the proteins that inhibit the differentiation maturation and normal function of DCs. The results of a phase I clinical study applying VEGF-trap to treat 15 patients with recurrent solid tumors showed that inhibition of the VEGF signaling pathway might induce differentiation and maturation of DC cells, but did not significantly enhance the body’s anti-tumor immune response [6]. Immunotherapy targeting MDSCs remains to be further investigated. 2. Induction of apoptosis or self-resistance to apoptosis Fas proteins belong to the TNF receptor family, and when combined with their ligands (Fas Ligand, FasL), they can induce apoptosis in cells expressing Fas proteins. In the process of anti-tumor immune response, activated specific T cells and NK cells express both FasL and Fas; while many tumor cells express high FasL on the surface, so tumor cells can mediate apoptosis of immune effector cells through FasL/Fas pathway, thus weakening the body’s anti-tumor immune response ability. The results of animal studies confirmed that down-regulation of FasL expression in tumor cells inhibits tumor growth and increases local infiltration of lymphocytes in tumor tissues [7]. Studies have shown that human solid tumor cells can express Toll-like receptors on their surface, which can promote tumor cell proliferation and inhibit their apoptosis [8]. Therefore, inhibiting the anti-apoptotic effect of tumor cells by down-regulating the abnormally expressed proteins on their surfaces may also be one of the therapeutic ideas to effectively reverse tumor immune escape. (II) Immune tolerance 1. The immunogenicity of tumor antigens is weak Tumor cells originate from their own body cells, and only a very small proportion of abnormally expressed proteins are immunogenic. Early studies have shown that the immunogenicity of spontaneous tumors is very weak, and it is difficult to stimulate the body to produce sufficient strength of immune response. While some of the tumor cells with strong immunogenicity were cleared after inducing the body’s anti-tumor immune response, the tumor cells with weak immunogenicity continued to proliferate after escaping the body’s immune surveillance. As a result, the immunogenicity of tumor cells becomes weaker and weaker. The application of tumor antigens can stimulate the body’s anti-tumor immune response by means of active immune response, in order to achieve the effect of treating tumor and preventing recurrence. However, there are not many tumor antigens applied in clinical practice. 2. Abnormal expression of major histocompatibility antigen Most tumor cells have reduced or absent expression of major histocompatibility antigen-Ⅰ (MHC-Ⅰ), which affects the formation of MHC-antigen peptide-TCR complex, and T cells cannot recognize tumor cell surface antigen, thus tumor cells evade the recognition and attack of immune cells. The expression of human leukocyte class I antigen (HLA-Ⅰ) was found to be reduced or even absent in human tumor tissues and cell lines, and the degree of HLA-Ⅰ decrease was positively correlated with tumor malignancy, metastasis and poor prognosis. It has been found that changes in MHC-Ⅰ expression affect the efficacy of tumor immunotherapy. MHC-Ⅰ expression increased in patients with immunotherapy-sensitive tumors compared to pre-treatment; while MHC-Ⅰ expression remained decreased in treatment-resistant patients [9]. It is suggested that the restoration of MHC-Ⅰ expression is the key to tumor immunotherapy [10]. However, the effect of soluble HLA-Ⅰ (sHLA-Ⅰ) on the body’s tumor immune response is two-sided. Studies have shown that sHLA-Ⅰ not only induces apoptosis in tumor cells, but also inhibits the activity of immune effector cells, such as cytotoxic T cells and NK cells, and induces their apoptosis [11, 12]. In addition, HLA-G was found to be expressed on the surface of some tumor cells.HLA-G, which is a non-classical HLA-Ⅰ, is mainly expressed in trophoblast cells outside the placental villi and mediates immune escape between the mother and fetus, allowing the embryo to implant and grow in the mother.Rouas-Freiss et al. showed that abnormal expression of HLA-G in tumor cells directly inhibits T cells, antigen-presenting cells ( In addition, HLA-G can also induce the formation of immunosuppressive cells [13]. Therefore, the mechanism and clinical application of MHC in tumor immune escape still need to be further investigated. 3. decreased expression of co-stimulatory and adhesion molecules Co-stimulatory and adhesion molecules play an important role in the adhesion and recognition between T/B cells and APC or tumor cells during the immune response. It has been found that APC and tumor cells in tumor patients are unable to induce immune response due to the lack of co-stimulatory molecules or reduced expression of adhesion molecules. There are many studies on upregulation of cellular co-stimulatory molecules or adhesion molecules by gene therapy, but the real application to clinical treatment is not common. 4. Tumor antigen processing and presentation disorder mainly refers to the dysfunction of DC antigen presentation in tumor patients, which is a dedicated APC with the strongest antigen presentation ability and is the main initiator of the body’s immune response, playing a key role in the immune response. Studies have shown that DCs in peripheral blood of tumor patients are dysfunctional in antigen presentation. In contrast, DCs expanded by co-culture with granulocyte/macrophage colony-stimulating factor (GM-CSF), IL-4, and tumor necrosis factor-α (TNF-α) from bone marrow cells were found to have good antigen-presenting function in vitro. It indicates that DCs in the tumor patient organism may be affected by the tumor microenvironment, which disturbs the maturation process of their release from the bone marrow to the periphery, thus weakening the ability to present tumor antigens. Studies have confirmed that APC cultured with cytokines in vitro after transfusion back into patients can effectively improve the antigen processing and presentation function of APC. (iii) Immune aging Studies have confirmed that the anti-tumor immune response capacity of the body’s immune system gradually decreases with age [14]. The mechanisms include the reduction of effector immune cells and the activation of immune tolerance signaling pathways. Immune senescence can significantly reduce the efficacy of immunotherapy in patients. Therefore, targeted administration of immune enhancers to adjuvant immunotherapy in elderly patients may improve the efficacy of this group of patients. New strategies for reversing tumor immune escape (a) Cytokines Through infusion of cytokines, the immune response of the body can be regulated, tumor cells can be directly killed, tumor cell proliferation can be inhibited and their differentiation and maturation can be promoted. The most commonly used cytokines in clinical antitumor immunotherapy include: IL-2, interferon (IFN), etc. IL-2 can promote the proliferation and differentiation of T cells and produce various lymphokines such as IFN-γ, IL-5, IL-6, TNF-β and CSF, etc. It can promote the proliferation and differentiation of B cells and the secretion of immunoglobulins through direct or indirect effects; it can induce a variety of immune effector cells such as cytotoxic T lymphocytes (CTL), NK cells and lymphokine-activated killer cells (LAK), etc. IL-2 is at the center of the cytokine-regulated immune response network and is important for the immune surveillance and anti-tumor immunity of the body. Currently, it is mainly used in the treatment of metastatic kidney cancer and malignant melanoma, and can achieve complete remission in 5-10% of patients. In addition, it is also used in bladder cancer, breast cancer, liver cancer, lymphoma and other malignant tumors through the combination with other cytokines and peripatetic cellular immunotherapy. Adverse effects include chills, fever, water retention, weight gain with capillary leak syndrome, etc. Paracetamol, anti-inflammatory pain and renal corticosteroids can be given before or during the treatment to reduce the adverse effects. IFN is divided into three categories: IFN-α, IFN-β and IFN-γ. IFN-α can be used in leukemia, malignant melanoma, lymphoma, kidney cancer, etc. IFN-γ has stronger immunomodulatory activity and is often used in combination with conventional cellular immunotherapy. Patients may have flu-like symptoms, fever, fatigue and headache, which are dose-related. (ii) Relay cellular immunotherapy Relay cellular immunotherapy is used to improve the body’s anti-tumor immunity through the infusion of anti-tumor immune effector cells. 1. Cytokine-induced killer cells (CIK) CIK therapy is a treatment method in which human peripheral blood mononuclear cells are activated in vitro by stimulation with various cytokines (CD3 monoclonal antibody, IL-2, IFN-γ, etc.) and then transfused back into the body. Its strong tumor-killing activity, broad tumor-killing spectrum and mild adverse effects are widely used in adjuvant therapy of tumors. 2. LAK cells LAK cells are immunocidal cells obtained from autologous or allogeneic peripheral blood lymphocytes after activation by cytokines (mainly IL-2). Their killing effect is somewhat non-specific, i.e., they have a broader spectrum of anti-tumor effects. The results of current clinical studies show that it is more effective against kidney cancer, malignant melanoma, lung cancer, nasopharyngeal carcinoma, leukemia, and non-Hodgkin’s lymphoma, but less effective against other solid tumors such as liver cancer and intestinal cancer. Its role is limited when the tumor load is large or when metastasis is present. However, it is more effective for the control of recurrence, metastasis, micro residual foci and malignant thoracic (ascites) fluid. 3. Tumor infiltrating lymphocytes (TIL) TIL cells refer to infiltrating lymphocytes with anti-tumor effect in tumor tissues. Currently, there are three main ways to obtain TIL cells: ① surgically resected or biopsied tumor tissue; ② lymphocytes in cancerous pleural fluid and ascites; ③ metastatic lymph nodes; TIL cells are complicated to isolate, easy to cause pollution, long culture time, and most tumor tissues contain very few TIL cells, and their culture success rate is only about 20%. Therefore, the clinical application is somewhat limited. (iii) Tumor vaccines with DC vectors DC vaccines include tumor antigen-sensitized DC vaccines and gene-modified DC vaccines. Provenge is composed of autologous peripheral blood mononuclear cells including APC, which are activated by prostatic acid phosphatase (PAP) and GM-CSF in vitro and then transfused back to patients. and transfused back into the patient. A placebo-controlled randomized, double-blind, multicenter phase III clinical study enrolled 512 patients with metastatic prostate cancer who had failed hormone therapy, of whom 341 were treated with Provenge (Q2 weeks × 3) [15]. Median survival time was significantly longer in the Provenge group compared with the placebo group (25.8m vs. 21.7m, P=0.03), with an increased 3-year survival rate (31.7% vs. 23.0%). There was no statistical difference in the objective time to disease progression between the two groups. Safety aspects (Provenge group): serious adverse reactions included acute infusion reaction (occurring on day 1 of cellular reinfusion) and cerebrovascular accident; grade 3 acute infusion reaction occurred in 3.5% of patients; no grade 4 or 5 adverse reactions occurred; the most common adverse reactions were chills, fatigue, fever, back pain, nausea, joint pain, and headache. To prevent adverse reactions, acetaminophen and antihistamines (e.g., diphenhydramine) may be administered orally 30 min prior to the infusion, and each infusion should last approximately 60 min. Provenge was approved by the FDA on April 29, 2010 for the treatment of metastatic prostate cancer and was included in the V.1.2011 edition of the NCCN guidelines, which recommend it for asymptomatic or less symptomatic metastatic prostate cancer with ECOG 0-1. III. Problems and Prospects The success of Provenge is an encouraging advancement in tumor immunotherapy, but the overall efficacy of tumor immunotherapy is currently not very satisfactory and has an adjuvant status in tumor treatment. Since various tumor immune escape mechanisms are always in a complex immune network, the ideas of therapeutic research must all avoid being limited to a certain type of antigenic peptide, a certain factor, or a certain cell. It is expected that as the research of tumor immune escape mechanism continues to be advanced, more and more new ideas of immunotherapy can be applied to clinical practice.