β‐Adrenergic Signaling Promotes Anti‐Tumor Immunity in TP53‐mutant Oral Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) is notoriously resistant to immunotherapy. The interplay between β-adrenergic signaling and p53 loss, both key regulators of immune responses, has remained largely unexplored in the setting of tumor-immune evasion. This study demonstrates that pharmacologic stimulation of β2-adrenergic receptors with isoprenaline significantly enhances cytotoxic T cell activity against p53-deficient HNSCC cells via a CXCL10-dependent paracrine mechanism. Comprehensive transcriptomic and co-culture assays reveal that p53-null cancer cells upregulate CXCL10, which promotes CD8⁺ T cell recruitment and activation. Neutralization of CXCL10 abolishes the β-adrenergic-induced cytotoxic T cell response, establishing this chemokine as a pivotal mediator. Using tyrosine hydroxylase knockout mouse models, we show that adrenergic innervation is essential for intra-tumoral CXCL10 expression and the infiltration of effector CXCR3⁺ T cells in vivo. Notably, the CXCL10-driven T cell response is associated with simultaneous upregulation of both activation and exhaustion markers, indicating a robust but transient effector state within the tumor microenvironment. Collectively, these findings uncover a neuro-immune axis that reverses immune escape in p53-deficient HNSCC and suggest novel therapeutic strategies targeting adrenergic signaling to convert immune "cold" tumors into "hot" ones more amenable to immunotherapy.