[IUPHAR review] Resistance to PD-1/PD-L1 blockade: mechanisms and pharmacological strategies.

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have transformed the realm of cancer treatment. Nevertheless, fewer than one in five patients derive durable benefit, and a substantial proportion of initial responders eventually relapse, reflecting a heterogeneous milieu of intrinsic and acquired mechanisms of resistance. Resistance to ICIs can arise from impaired neoantigen generation and presentation (low tumor mutational burden, loss of functional HLA class I and β2-microglobulin), defective IFN-γ/JAK-STAT signaling, co-expression of alternative checkpoints (LAG-3, TIM-3, TIGIT, CTLA-4), an immunosuppressive and metabolically hostile "cold" tumor microenvironment enriched in regulatory T cells, myeloid-derived suppressor cells, and M2-polarized macrophages, and clonal immunoediting. In this review, we synthesize the current landscape of PD-1/PD-L1-directed ICIs, dissect the molecular and cellular determinants of intrinsic and acquired resistance, and discuss emerging pharmacological strategies to overcome them, including next-generation checkpoint combinations (anti-LAG-3, anti-TIGIT), bispecific antibodies (e.g., PD-1/VEGF, PD-L1/TGF-β), antibody-drug conjugates, targeted-therapy and epigenetic combinations, innate immune agonists, oncolytic viruses, gut microbiome modulation, and biomarker-guided patient selection, with the goal of informing rational combination regimens capable of extending the benefit of checkpoint blockade to a substantially broader patient population.