Iron homeostasis and macrophage polarization in oral squamous cell carcinoma: mechanisms and therapeutic perspectives.

Oral squamous cell carcinoma (OSCC) is an aggressive malignancy with a profoundly immunosuppressive tumor microenvironment and persistently poor responses to immune checkpoint inhibitors. Recent evidence highlights dysregulated iron metabolism as a critical yet underrecognized driver of this immunosuppressive state. Excess intratumoral iron perturbs macrophage polarization toward pro-tumoral M2-like phenotypes through iron-sensing pathways, including HIF-1α stabilization, IL-10/STAT6 signaling, and NF-κB-mediated redox programs, driving T-cell suppression, angiogenesis, and extracellular matrix remodeling that collectively reinforce resistance to PD-1/PD-L1 checkpoint blockade. Concurrently, iron-dependent regulated cell death via ferroptosis - governed by the GPX4-glutathione-system Xc- axis - represents an emerging immunological vulnerability, as ferroptotic tumor cells release damage-associated molecular patterns that potentiate anti-tumor CD8+ T-cell responses and synergize with checkpoint inhibitor activity. This review synthesizes current findings on the mechanistic interplay between iron homeostasis, macrophage phenotypic switching, and ferroptosis in OSCC and evaluates emerging therapeutic strategies targeting this axis, including iron chelators, ferroportin modulators, ferroptosis inducers, Nrf2 pathway inhibitors, exosome-mimetic delivery systems, and iron-based nanoplatforms. While these approaches show promise, challenges remain regarding TME specificity, off-target iron depletion, and the absence of validated biomarkers for patient stratification. By integrating mechanistic insights with translational advances, this review underscores the therapeutic potential of targeting the iron-macrophage-ferroptosis axis and outlines how precision medicine-based interventions may overcome immune evasion and improve immunotherapy outcomes in OSCC.