The hypoxic tumor microenvironment: Functional and metabolic reprogramming of key immune populations

Tumor-induced hypoxia remains a pivotal characteristic of the tumor microenvironment (TME), significantly impacting immune cell functionality by fostering immunosuppression, tumor advancement, and resistance to therapies. This review consolidates established and emerging insights into how hypoxia, chiefly orchestrated by hypoxia-inducible factors (HIFs), metabolically and functionally reprograms key immune populations such as B cells, CD4 + T-cells, CD8 + T-cells, natural killer (NK) cells, regulatory T-cells (Tregs), and macrophages. We examine hypoxia-driven metabolic adaptations, signaling alterations, and evasion strategies, including enhanced glycolysis, lactate accumulation, and immune checkpoint upregulation. Furthermore, we integrate cutting-edge findings, such as hypoxia's modulation of NK cell cytotoxicity, immune metabolic reprogramming in the TME, HIF-mediated immune modulation, effector T-cell transcriptomic shifts akin to non-responsive tumor-infiltrating lymphocytes, and autophagy-dependent MHC-I suppression for immune evasion. These advancements underscore therapeutic opportunities in targeting hypoxia to bolster antitumor immunity and mitigate immunotherapy resistance in cancer.