Hypoxia-Driven Immune Resistance to Anti-PD-1/PD-L1 Therapy: Mechanistic Insights and Therapeutic Opportunities

Immune checkpoint blockade targeting programmed death protein-1 (PD-1) and its ligand PD-L1 has shown substantial therapeutic benefit in only a subset of patients with solid tumors, highlighting the urgent need to improve cancer immunotherapy outcomes. Hypoxia, a hallmark of the tumor microenvironment (TME), plays a critical role in modulating antitumor immunity and contributes to resistance against PD-1/PD-L1 blockade. Hypoxia influences multiple microenvironmental factors, affecting disease progression, treatment responses, and prognosis in solid tumors. As a result, hypoxia has emerged as a pivotal therapeutic target in combination immunotherapy approaches. This review explores the molecular and cellular mechanisms by which the hypoxic TME induces resistance to PD-1/PD-L1 blockade across distinct tumor types. Furthermore, we examine current strategies that target hypoxia to enhance immunotherapy efficacy and discuss the potential benefits of combination regimens. Collectively, this study provides a comprehensive framework for the rational design and clinical optimization of PD-1/PD-L1 inhibitors, with the goal of expanding their therapeutic applicability in solid malignancies.