Exploiting the CXCR3/CXCL10 axis overrides tumor immune suppression by enhancing immune trafficking and effector cell priming in HNSCC.

Immune-suppressive tumor microenvironments (TMEs) limit the impact of checkpoint blockade in many cancers by restricting the infiltration and activation of CD8+ T, CD4+ T, and NK cells. Utilizing murine models of head and neck squamous cell carcinoma, we demonstrated that intratumoral (IT) delivery of CXCL10 drives tumor elimination and inhibits recurrence not only by recruiting these cells but by enhancing their antitumoral functions and stunting angiogenesis. CD8+ T cells also display enhanced activation, tumor-antigen specificity, and decreased T cell exhaustion. Despite administration of CXCL10 into tumors, CD8+ and CD4+ T cells show enhanced presence and proliferation in tumor-draining lymph nodes (TdLNs), consistent with T cell priming and trafficking between tumors and TdLNs. Together, the data suggest that CXCL10 promotes a mutually reinforcing feedback loop that reprograms the TME toward an immunologically responsive antitumoral state. Combining IT-CXCL10 and anti-PD-1 further increased tumor clearance, indicating that CXCL10-driven reprogramming of the TME lowers barriers to effective checkpoint blockade.