Targeting the hypoxia signaling pathway with nanomedicine to reverse immunotherapy resistance

Immunotherapy has emerged as a major therapeutic strategy for cancer; however, immunotherapy resistance remains a significant challenge. Hypoxia, a key hallmark of the tumor microenvironment resulting from the imbalance between the high oxygen demand of rapidly proliferating cancer cells and the limited supply from abnormal blood vessels, plays a central role in driving immunotherapy resistance. Hypoxia-inducible factor-1a (HIF- 1α) and its downstream signaling pathways contribute to this resistance by promoting macrophage polarization toward the protumorigenic M2 phenotype, inducing T cell exhaustion, facilitating immune evasion, enhancing angiogenesis, and activating other resistance mechanisms. The review highlights the mechanisms by which hypoxia regulates resistance to immunotherapy and provides a comprehensive overview of nanotechnology-based strategies designed to counteract hypoxia-induced resistance. Finally, the prospects and challenges of translating nanomedicine-based drug delivery systems into clinical practice for overcoming immunotherapy resistance are outlined.