Mechanisms, combination therapy, and biomarkers in cancer immunotherapy resistance

Anti-programmed death 1/programmed death ligand 1 (anti-PD-1/PD-L1) antibodies exert significant antitumor effects by overcoming tumor cell immune evasion and reversing T-cell exhaustion. However, the emergence of drug resistance causes most patients to respond poorly to these immune checkpoint inhibitors (ICIs). Studies have shown that insufficient T-cell infiltration, lack of PD-1 expression, deficient interferon signaling, loss of tumor antigen presentation, and abnormal lipid metabolism are all considered to be closely associated with immunotherapy resistance. To address drug resistance in tumor immunotherapy, a lot of research has concentrated on developing combination therapy strategies. Currently, ICIs such as anti-PD-1 /PD-L1 antibody combined with chemotherapy and targeted therapy have been approved for clinical treatment. In this review, we analyze the mechanisms of resistance to anti-PD-1/PD-L1 therapy in terms of the tumor microenvironment, gut microbiota, epigenetic regulation, and co-inhibitory immune checkpoint receptors. We also discuss various promising combination therapeutic strategies to address resistance to anti-PD-1/PD-L1 drugs, including combining these therapies with traditional Chinese medicine, non-coding RNAs, targeted therapy, other ICIs, and personalized cancer vaccines. Moreover, we focus on biomarkers that predict resistance to anti-PD-1/PD-L1 therapy as well as combination therapy efficacy. Finally, we suggest ways to further expand the application of immunotherapy through personalized combination strategies using biomarker systems.