The PD-1/PD-L1 axis in cancer: from immune evasion mechanisms to next-generation therapeutics

Immune checkpoint blockade directed against the programmed cell death protein 1 (PD-1) receptor and its ligand PD-L1 has markedly transformed cancer therapy, producing sustained clinical benefit and prolonged survival in selected patient populations across multiple tumor types. However, clinical responses remain highly heterogeneous, largely limited by low overall response rates, the development of both intrinsic and acquired resistance, and immune-related toxicities that restrict the durability of single-agent treatment. In this article, we systematically examine the PD-1/PD-L1 axis from a mechanistic perspective, spanning its roles in tumor initiation, disease progression, metastatic spread, and immune escape. We detail how PD-1/PD-L1 axis drives T cell exhaustion, impairs antigen presentation, reshapes the immunosuppressive tumor microenvironment, and promotes epithelial–mesenchymal transition (EMT), thereby enabling immune escape throughout tumor evolution. We further catalog recent innovations in PD-1/PD-L1-targeted therapeutics, spanning monoclonal antibodies, bispecific molecules, Fc-optimized biologics, and novel synthetic modalities—including RNA interference, CRISPR-based gene editing, antisense oligonucleotides, and mRNA platforms. In addition, we evaluate emerging small-molecule inhibitors designed to directly disrupt PD-1/PD-L1 engagement, modulate checkpoint expression transcriptionally or post-translationally, and reprogram oncogenic, metabolic, and epigenetic circuits to circumvent resistance. A dedicated focus is placed on deciphering adaptive and intrinsic resistance mechanisms, such as PD-L1 re-induction, T cell dysfunction, deficits in antigen presentation, and compensatory upregulation of alternative immune checkpoints (e.g., LAG-3, TIM-3, TIGIT). We also examine rationale-driven combination approaches that integrate checkpoint inhibitors with targeted agents, chemotherapy, metabolic modulators, and epigenetic drugs to amplify antitumor immunity. Taken together, this review proposes an integrated framework for understanding the diverse roles of the PD-1/PD-L1 axis in tumor–immune interactions and offers strategic guidance for the development of next-generation checkpoint inhibitors and precision immunotherapy approaches.