Cancer Genetics and Epigenetics, 2025, Vol.13, No.6, 300-309 http://medscipublisher.com/index.php/cge 301 2 Mechanism of Immune Checkpoint Inhibitors 2.1 Inhibition of PD-1/PD-L1 pathways and representative drugs Programmed cell death protein 1 (PD-1) and its ligand PD-L1 are key immune checkpoint pathways for tumors to evade the surveillance of the immune system. PD-1 appears on the surface of activated T cells, while PD-L1 usually increases on tumor cells and immune cells around tumors, which leads to the decline of T cell function and the weakening of the ability to fight tumors (Topalian et al., 2012). Immune checkpoint inhibitors (ICIs) such as pembrolizumab, nivolumab and atezolizumab can block the binding of PD-1 to PD-L1, restore the function of T cells, and thereby help kill tumor cells. The clinical development of PD-1/PD-L1 inhibitors has changed the treatment approaches for various solid tumors, including non-small cell lung cancer, melanoma and renal cell carcinoma. These drugs have demonstrated sustained therapeutic effects in multiple important trials and improved patient survival rates. They have now become essential drugs in tumor treatment (Gandhi et al., 2018). The success of these drugs also indicates that the PD-1/PD-L1 pathway plays a core role in tumor immune escape, and blocking this pathway has great therapeutic value. 2.2 The immunomodulatory effect of the CTLA-4 pathway and its therapeutic advantages Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is another key immune checkpoint that regulates the activation of early T cells. It competes with the co-stimulatory receptor CD28, binds to the B7 molecule (CD80/CD86) on antigen-presenting cells, and then transmits inhibitory signals, thereby suppressing the immune response of T cells. Drugs such as ipilimumab can promote the activation and proliferation of T cells by blocking CTLA-4, thereby enhancing the body's immune ability against tumors (Hodi et al., 2010). Targeted therapy against CTLA-4 has been proven to have clinical efficacy, especially in the treatment of melanoma. Ipilimumab was the first ICI found to improve the overall survival rate of patients in a phase III trial (Hodi et al., 2010). Compared with PD-1/PD-L1 inhibitors, the mechanism of action of CTLA-4 blockers is very special, mainly exerting its function in the initiation stage of the immune response. This provides theoretical support for the combination therapy strategy, and better synergistic anti-tumor effects can be achieved through combined use. 2.3 The mechanism basis of emerging targets (such as TIGIT, LAG-3, etc.) and joint checkpoint blocking strategies In addition to PD-1/PD-L1 and CTLA-4, researchers have also identified other new immune regulatory molecules, such as TIGIT and LAG-3, which also play significant roles in controlling the body's immune response to tumors. TIGIT reduces the activity of T cells and natural killer cells by binding to CD155, while LAG-3 restricts the proliferation of T cells and the generation of cytokines. Existing animal experiments and early clinical studies have shown that blocking these molecular pathways can further enhance the body's anti-tumor ability, especially for those tumor types that have a poor response to PD-1/PD-L1 or CTLA-4 inhibitors. The theoretical basis of the joint checkpoint blockade strategy lies in the fact that these inhibitory signals can complement each other, and sometimes even none of them can be absent. By simultaneously blocking two or more checkpoints, for example, using anti-PD-1 drugs in combination with anti-CTLA-4 or anti-LAG-3 drugs, a stronger synergistic effect can be produced in multiple tumors and the therapeutic effect of patients can be improved (Larkin et al., 2019; Tawbi et al., 2022). At present, multiple related studies are being carried out to further confirm the safety and efficacy of these combined regimens, and it is hoped that this will solve the problem of drug resistance and enable more patients to benefit from immunotherapy. 3 The Therapeutic Effect of ICIs in Major Solid Tumors 3.1 It significantly prolongs the survival of patients with lung cancer and melanoma Immune checkpoint inhibitors (ICIs) have significantly transformed the treatment landscape for non-small cell lung cancer (NSCLC) and melanoma, prolonging the survival time of more patients compared to traditional treatments. In non-small cell lung cancer, key studies such as KEYNOTE-024 and KEYNOTE-189 have shown
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