From signals to phenotype: multifactorial drivers of tumor-associated macrophage polarization in oral cavity squamous cell carcinoma: a narrative review.

PURPOSE: This narrative review aimed to integrate oral cavity squamous cell carcinoma (OSCC)-specific evidence on the signals shaping the spatial and functional heterogeneity of tumor-associated macrophages (TAMs) and to evaluate their implications for tumor progression, treatment response, biomarker development, and therapeutic targeting. METHODS: PubMed/MEDLINE, Scopus, and Web of Science were searched from database inception to July 15, 2026, for mechanistic, spatial, preclinical, translational, and clinical studies concerning TAM recruitment, polarization, tumor-macrophage crosstalk, biomarkers, and TAM-directed interventions in OSCC. Broader head and neck squamous cell carcinoma evidence was considered only when directly relevant OSCC-specific evidence was limited. RESULTS: The available evidence supports a continuum model of macrophage activation rather than a rigid M1/M2 classification. Hypoxia, lactate accumulation, cytokine and chemokine signaling, cancer-associated fibroblasts, extracellular-matrix remodeling, extracellular vesicles, and oral microbial cues converge to generate heterogeneous TAM states. These states can promote immune suppression, angiogenesis, epithelial-mesenchymal plasticity, invasion, metastatic niche formation, and resistance to immunotherapy or radiochemotherapy. CD163- and CD206-enriched macrophage populations are frequently associated with adverse clinicopathologic features, whereas treatment-related changes in macrophage composition may provide exploratory response-associated or pharmacodynamic information. Preclinical studies further indicate that disrupting recruitment, survival, metabolic, microbial, or vesicle-mediated feedback circuits, or reprogramming suppressive TAMs, can reduce tumor-promoting activity. CONCLUSION: TAMs should be evaluated as spatially organized, functionally diverse, and treatment-responsive populations. Clinically useful biomarkers and therapeutic approaches will require standardized, function-based characterization and prospective validation of rational combinations with immunotherapy and radiochemotherapy.