The CGRP-nociceptor axis in cancer: tumor-specific programs of immune evasion, stromal remodeling, and tumor growth

Cancer neuroscience has established that peripheral nerves can shape tumor growth and antitumor immunity, although the underlying mechanisms vary across malignancies. Calcitonin gene-related peptide (CGRP), released mainly by peptidergic nociceptors and sensed through the CALCRL/RAMP1 receptor complex, is emerging as a recurrent mediator of tumor-nerve communication. This review synthesizes current evidence for CGRP signaling across tumor types. In melanoma and head and neck squamous cell carcinoma (HNSCC), CGRP can directly suppress tumor-infiltrating T cell activity. In lung adenocarcinoma, it acts through a macrophage-fibroblast relay that limits tertiary lymphoid structure assembly. In medullary thyroid cancer, tumor-associated CGRP is linked to abnormal dendritic cell development. In pancreatic ductal adenocarcinoma, nociceptor-derived CGRP participates in a reciprocal interaction with cancer-associated fibroblasts that lowers IL-15 and suppresses natural killer cells. Additional studies identify tumor-intrinsic outputs, including gastric tumor growth, CGRP-dependent cytoprotective autophagy in oral cancer, and RAMP1-dependent growth in gastrointestinal cancer models. Liver data currently support a role in fibrogenesis, while the relevance of this pathway to hepatocellular carcinoma remains unresolved. Together, these findings support a shared nociceptor-CGRP signaling system with tumor-specific cellular outputs. CGRP-pathway drugs and nociceptor-directed interventions therefore warrant tumor-specific translational studies, although anticancer efficacy remains predominantly preclinical.