Overcoming resistance to anti-PD-1/PD-L1 therapy in cancer.

Recently, programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors have achieved major breakthroughs in oncology, with 32 drugs approved over the past decade. This advancement has established immunotherapy as the fifth major antitumor modality following surgery, chemotherapy, radiotherapy, and targeted therapy. However, PD-1/PD-L1 inhibitors induce sustained responses in only a limited number of patients, and primary and acquired resistance remain critical challenges in clinical practice. As understanding of the complex crosstalk among cancer cells, the tumor microenvironment, and the host immune system deepens, numerous strategies to overcome PD-1/PD-L1 inhibitor resistance have been proposed. In this review, we examine the current development of PD-1/PD-L1 inhibitors, analyze global approval trends, and evaluate their monotherapy efficacy across various tumor types. As multi-target combination therapy is an essential strategy for overcoming resistance, we analyze key combination targets - such as vascular endothelial growth factor (VEGF), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and lymphocyte activation gene 3 (LAG-3) - and highlight the clinical success of novel dual-target regimens such as ivonescimab (PD-1/VEGF). Furthermore, we discuss potential approaches to overcoming resistance from both microenvironmental (e.g., targeting cancer-associated fibroblasts or utilizing antibody-drug conjugates) and macroenvironmental (e.g., modulating the microbiota or sex hormones) perspectives. This review provides a forward-looking framework for designing precision- and mechanism-driven combination therapies aimed at converting non-responders into responders.