CGRP signaling links tumor-associated pain to immune evasion in oral squamous cell carcinoma

Peripheral sensory nerves are thought to play a role in solid tumor growth, particularly in oral squamous cell carcinoma (OSCC); however, the link between pain and immunosuppression remains unresolved. Here, we find an inverse relationship between OSCC-associated pain by way of calcitonin gene-related peptide (CGRP)-expressing nerves and tumor-associated immunity in patients with OSCC. Bulk RNA sequencing of tumor-innervating sensory neurons from syngeneic mouse models of OSCC shows differential regulation of genes associated with excitability, neurotransmission, and axonal sprouting. Using a gain-of-function approach by persistently stimulating peptidergic afferents, we show that sensory neurons support the growth of oral tongue tumors and limit the activation of an effective anti-tumor immune response via efferent CGRP release. Loss-of-function approaches, such as local ablation of nociceptive nerves or systemic CGRP receptor antagonism, slow tumor growth and improve anti-tumor immunity. Targeting CGRP may serve as a potential therapeutic strategy in OSCC to reduce pain and improve therapeutic response.