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

作者：Frederico O. Gleber‐Netto, Deborah A. Silverman, Tongxin Xie, Shamima Akhter, Nicole Vaughn, Adewale Adebayo, Kala Chand Debnath, Shorook Naara, Shajedul Islam, Erik Knutsen, Emily Lorin Ashkin, Simone Anfossi, Sara Elizabeth Leahey, Patrick Hwu, Sébastien Talbot, Erica K. Sloan, Robert Saddawi‐Konefka, Roberto Rangel, Jeffrey N. Myers, George A. Calin, Moran Amit · 发表于：Advanced Science · 年份：2026 · DOI：10.1002/advs.202516859 · 被引用次数：2 · 研究领域：Cancer, Stress, Anesthesia, and Immune Response、Chemokine receptors and signaling、Cancer Research and Treatments

ABSTRACT 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.