Cancer-induced Nerve Injury Unveils a Sympathetic-to-Sensory Nerve Axis in Head and Neck Cancer

Oral squamous cell carcinoma (OSCC) is one of the most painful cancers, with patients frequently reporting spontaneous, neuropathic-like pain. While sympathetic and sensory nerves have been individually implicated in cancer progression, whether and how these systems interact to drive pain and tumor growth has remained unclear. Here, we integrate prospective human data with reverse-translational mouse models to reveal that cancer-induced nerve injury unveils crosstalk between sympathetic postganglionic neurons and trigeminal sensory afferents in the tumor microenvironment. In patients, circulating norepinephrine (NE) correlated with spontaneous pain and perineural invasion, identifying a potential sympathetic contribution to disease burden. In mice, aggressive non-immunogenic OSCC tumors evoked spontaneous nociceptive behaviors, elevated tumoral NE, and sensory nerve injury marked by ATF3 expression and hyperexcitability. Tumor-associated sensory neurons acquired adrenergic sensitivity through 1-adrenergic receptor plasticity, while sympathetic neurons exhibited plasticity characterized by sprouting, altered gene expression, and heightened excitability, creating a maladaptive feed-forward loop that amplified nociceptive signaling. Disrupting this sympathetic-sensory communication by sympathectomy or selective ablation of TRPV1 sensory fibers reduced tumor growth, sympathetic tone, and spontaneous pain like behaviors, although sensory adrenergic sensitivity persisted. Together, these findings establish that reciprocal sympathetic-sensory plasticity and crosstalk in the tumor may fuel both OSCC progression and neuropathic like pain. Targeting this peripheral neuroplasticity may offer a translational strategy to limit tumor growth and alleviate pain. One Sentence SummaryReciprocal plasticity and crosstalk between sympathetic and sensory nerves drive both tumor progression and neuropathic-like pain in oral squamous cell carcinoma, suggesting peripheral neuroplasticity as a therapeutic target.