CGRP signaling Links Tumor-Associated Pain to Immune Evasion in Oral Squamous Cell Carcinoma

Peripheral sensory nerves are thought to contribute to solid tumor growth, particularly in oral squamous cell carcinoma (OSCC); however, the link between pain and immunosuppression remains unresolved. Here, using a prospective observational study, we demonstrate an inverse relationship between OSCC-induced pain mediated by calcitonin gene-related peptide (CGRP)-expressing nerves and tumor-associated immunity. Bulk RNA sequencing of tumor-innervating sensory neurons from mice revealed differential regulation of genes associated with excitability, neurotransmission, and axonal sprouting. Using a gain-of-function approach with persistent stimulation of peptidergic afferents, we show that sensory neurons promote oral tongue tumor growth and limit the activation of effective anti-tumor immune responses via efferent CGRP release. Conversely, loss-of-function approaches—including local ablation of nociceptive nerves and systemic CGRP receptor antagonism—slowed tumor growth and improved anti-tumor immunity. Targeting CGRP may therefore represent a therapeutic strategy in OSCC to reduce pain and improve treatment response.