Resistance mechanisms and reversal strategies of PD-1/PD-L1 inhibitors in melanoma

Abstract

Programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint inhibitors have redefined the therapeutic landscape of advanced melanoma, establishing a first-line standard of care that markedly prolongs patient survival. Nevertheless, primary and acquired resistance remain the principal barriers to durable clinical benefit: approximately 40%–55% of patients exhibit primary resistance to PD-1 monotherapy inhibitors, while 25%–30% of initial responders develop acquired resistance during treatment. Resistance arises from multidimensional, interconnected mechanisms spanning tumor-intrinsic alterations, immunosuppressive tumor microenvironment remodeling, metabolic and epigenetic reprogramming, and systemic modulators including the gut microbiota. By linking antigen recognition, spatiotemporal regulation, and clinical translation, this review provides a mechanistic framework for understanding PD-1/PD-L1 inhibitor resistance in melanoma. This review aimed to systematically evaluate the evidentiary basis for resistance-reversal strategies—encompassing immune combinations, targeted agents, cellular therapies, and localized interventions—and consolidate hierarchical biomarker systems with translational potential. Critical gaps in clinical applicability, including patient selection, treatment sequencing, and combination-related toxicity, are discussed. Finally, the review highlights unresolved challenges and future directions to guide precision optimization of melanoma immunotherapy.