Hypoxia-inducible factors as central orchestrators of immune evasion in head and neck squamous cell carcinoma: mechanisms and therapeutic strategies

Hypoxia is a hallmark feature of the tumor microenvironment in head and neck squamous cell carcinoma (HNSCC). Hypoxia-inducible factor-1α (HIF-1α) and hypoxia-inducible factor-2α (HIF-2α) are frequently overexpressed across multiple subtypes of head and neck tumors and are strongly associated with poor prognosis. While immune checkpoint inhibitors (ICIs) have revolutionized treatment for recurrent/metastatic HNSCC, their objective response rate (ORR) remains limited to 14%–22%. Notably, tumors with significant hypoxia exhibit particularly poor responses to immunotherapy, indicating that hypoxia-driven immune evasion is a critical bottleneck that limits treatment efficacy. The molecular mechanisms by which the HIF pathway mediates immune evasion in head and neck cancer can be summarized as follows. First, HIF-1α directly upregulates PD-L1 through transcriptional activation and cooperates with the adenosine pathway to induce T cell exhaustion. Furthermore, HIF-1α drives the Warburg effect, leading to lactate-driven acidification of the microenvironment and glucose competition that directly impair T cell function. In addition, HIF-1α confers resistance to ferroptosis and provides autophagy-mediated protection, enabling tumor cells to evade immune-mediated killing. Through the PI3K/Akt/β-catenin, STAT3, and Notch signaling networks, HIF drives EMT, conferring an immunosuppressive, stem-like phenotype upon tumor cells. Additionally, the HIF/vascular endothelial growth factor (VEGF) axis drives abnormal angiogenesis that hinders T cell homing and infiltration, establishing an immune-excluded microenvironment. HIF also regulates exosome biogenesis and delivers PD-L1 and microRNA (miRNA) to remodel distant immune cell phenotypes. Combining HIF pathway targeting with immune checkpoint inhibitors may offer a promising strategy to overcome immunotherapy resistance.