CAR-T cell therapy for solid tumors: HIF-1α as a potential enhancement strategy

The advent of chimeric antigen receptor (CAR) T cell therapy has yielded transformative efficacy in hematological malignancies, yet its application in solid tumors remains constrained by the immunosuppressive tumor microenvironment (TME). Characterized by hypoxia, acidosis, and nutrient deprivation, the TME critically compromises CAR-T cell infiltration, persistence, and effector functions. Hypoxia-inducible factor 1α (HIF-1α), a central regulator of cellular adaptation to hypoxia within the TME, modulates T cell metabolism and functionality-presenting a strategic framework for enhancing CAR-T cell efficacy in solid malignancies. This review characterizes the role of HIF-1α in reprogramming the tumor-immune microenvironment, with specific emphasis on its metabolic regulation of T cells and translational implications for CAR-T therapy. Under hypoxic stress, HIF-1α orchestrates a metabolic shift toward glycolysis in effector T cells by suppressing oxidative phosphorylation (OXPHOS) while upregulating key glycolytic enzymes (e.g. GLUT1, HK2, LDHA). This adaptation sustains ATP production while attenuating mitochondrial reactive oxygen species (ROS) accumulation, thereby mitigating T cell exhaustion and augmenting cytotoxic persistence. This HIF-1α-mediated metabolic reprogramming provides critical insights for overcoming barriers to CAR-T cell efficacy in solid tumors.