Spatial heterogeneity of MDSCs mediated by ANXA1-FPRs signaling drives immune suppression in OSCC progression.

Limited efficacy of immunotherapy in oral squamous cell carcinoma (OSCC) is driven by an immunosuppressive tumor microenvironment, yet the role of intratumoral spatial heterogeneity in immune responses remains unclear. Here, we employ single-cell and spatial transcriptomics to dissect the cellular composition and spatial organization of OSCC. We find CD8(+) T cells are spatially localized yet functionally suppressed in late-stage OSCC, while myeloid-derived suppressor cells (MDSCs) transition from tumor core infiltration in early-stage OSCC to marginal localization with CD8(+) T cells in advanced stages. ANXA1-FPR2 signaling mediates tumor-MDSCs communications, sustaining MDSCs recruitment and immune suppression. Disrupting ANXA1-FPR2 with an antagonist enhances the efficacy of immune checkpoint blockade therapy in OSCC mouse models. These findings reveal the spatial dynamics of MDSCs as key modulators of immune suppression and therapeutic resistance, offering a promising target to improve immunotherapy outcomes in OSCC.