Addressing resistance to immune checkpoint inhibitor therapy: an urgent unmet need.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of various cancers by reversing the immunosuppressive mechanisms employed by tumors to restore anticancer immunity. Although ICIs have demonstrated substantial clinical efficacy, patient response can vary in depth and duration, and many do not respond at all or eventually develop resistance. ICI resistance mechanisms can be tumor-intrinsic, related to the tumor microenvironment or patient-specific factors. Multiple resistance mechanisms may be present within one tumor subtype, or heterogeneity exists among patients with the same tumor type. Consequently, designing effective combination treatment strategies is challenging. This review will discuss ICI resistance mechanisms, and summarize findings from key preclinical and clinical trials of ICIs, to identify potential treatment strategies or pathways to overcome ICI resistance.