Cancer Genetics and Epigenetics, 2025, Vol.13, No.6, 300-309 http://medscipublisher.com/index.php/cge 306 Similarly, the combination of ICIs and targeted drugs (such as tyrosine kinase inhibitors) also shows potential in tumors such as renal cell carcinoma. The KEYKEYNOTE 426 trial demonstrated that pembrolizumab combined with axitinib (an anti-angiogenic targeted drug) had better survival outcomes than sunitinib monotherapy (Rini et al., 2019). These results suggest that the rational design of combination regimens is expected to overcome the problem of drug resistance and enable more patients to benefit from immunotherapy. 6.2 Mechanism and clinical effect of ICIs combined with radiotherapy or anti-angiogenic therapy Radiotherapy can cause immunogenic cell death and promote the exposure of tumor antigens, which provides a theoretical basis for its combination with ICIs. Preclinical studies have shown that radiotherapy can increase PD-L1 expression and enhance T cell entry into tumors, thereby enhancing sensitivity to PD-1/PD-L1 inhibitors. In the early clinical studies of lung cancer and head and neck cancer, radiotherapy combined with ICIs can improve the treatment response rate, and sometimes even shrinkage of unirradiated lesions has been observed (Theelen et al., 2019). Anti-angiogenic drugs (such as VEGF inhibitors) can regulate tumor vascular structure and reduce immunosuppressive cells, thereby further enhancing the effect of ICIs. The IMpower150 trial confirmed that adding atezolizumab to bevacizumab and chemotherapy could significantly increase the survival time of patients with non-small cell lung cancer, supporting the clinical application of this combination regimen (Socinski et al., 2018). These strategies demonstrate how mechanism research can drive the development of collaborative treatment models. 6.3 Dual immune blockade (such as PD-1+CTLA-4, PD-1+LAG-3) and new efficacy trends Simultaneously blocking two immune checkpoints, such as the combined use of PD-1 and CTLA-4 inhibitors, can activate the immune system through multiple pathways and exert a synergistic anti-tumor effect. In the CheckMate 067 trial of advanced melanoma, nivolumab combined with ipilimumab significantly improved the response rate and survival rate compared with monotherapy, although side effects also increased (Larkin et al., 2019). Currently, this combined approach is being studied in other tumors such as renal cell carcinoma and lung cancer, and has shown preliminary positive results (Motzer et al., 2018). New immune targets, such as LAG-3 and TIGIT, are also being attempted to be used in combination with PD-1 inhibitors to help overcome drug resistance and further enhance therapeutic effects. The relative-047 trial demonstrated that nivolumab combined with relatlimab (an anti-LAG-3 antibody) could further prolong progression-free survival in patients with advanced melanoma compared with nivolumab alone (Tawbi et al., 2022). These research advancements indicate that dual-target or multi-target immune blockade approaches are expected to be applied to the treatment of more solid tumors in the future. 7 Challenges and Future Directions 7.1 Scientific challenges brought about by treatment differences and drug resistance issues Although immune checkpoint inhibitors have improved the treatment approaches for various solid tumors, there are still significant differences in treatment outcomes among different patients, which remains an important challenge. Factors such as the number of tumor mutations, the extent to which immune cells enter the tumor, and the different compositions of the tumor microenvironment can all lead to inconsistent therapeutic effects among patients and among different types of cancer. Furthermore, some patients have no response from the start of treatment (i.e., primary drug resistance), which also limits the proportion of the population that can benefit from immunotherapy. There is also a portion of patients who initially have a good response, but their condition deteriorates again later (acquired drug resistance), which makes long-term disease control even more difficult. The emergence of drug resistance may be related to factors such as the decreased antigen-presenting ability of tumor cells, the enhancement of other immunosuppressive pathways, or the increase of inhibitory immune cells in the tumor microenvironment. To address these issues, we need to gain a deeper understanding of the interaction between tumors and the immune system and continue to seek new methods that can break through drug resistance.
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