Tumor microenvironment-driven immune evasion and therapeutic strategies in head and neck squamous cell carcinoma

PURPOSE OF REVIEW: Head and neck squamous cell carcinoma (HNSCC) develops within a complex tumor microenvironment (TME) that fosters immune evasion and limits the efficacy of immune checkpoint inhibitors (ICIs). Despite advances, durable responses to ICIs remain limited, partly because of stromal barriers, myeloid cell recruitment, and metabolic constraints within the TME. RECENT FINDINGS: Multiplex IHC/mIF, single-cell and spatial omics, and computational TME profiling reveal recurrent resistance programs, including CAF-driven immune exclusion, chemokine-dependent and hypoxia-dependent recruitment of myeloid cells and regulatory T cells, and nutrient and oxygen competition that constrain effector T cells. These insights underpin emerging TME-targeted combinations with PD-(L)1 blockade, such as VEGFR/multikinase and TGF-β/CAF-directed agents, myeloid and chemokine modulators, and metabolic interventions now being tested in solid tumors and increasingly in HNSCC. SUMMARY: The HNSCC TME is both a central barrier and an attractive therapeutic target. Embedding high-resolution TME profiling into clinical trials will be crucial to select TME-matched combinations and identify patient subsets most likely to derive durable benefit from immunotherapy.