CGRP: the immune system's double agent - context-dependent roles in inflammation, resolution and cancer.

Calcitonin gene-related peptide (CGRP) is traditionally recognized as a key mediator of nociception and vasodilation. However, it also functions as a context-dependent immune "double agent," capable of both restraining inflammation and driving pathological responses. Here we discuss CGRP multifaceted roles in innate and adaptive immunity, inflammation, resolution, infection, autoimmunity, and cancer. In the innate immune response, CGRP predominantly exerts anti-inflammatory and tolerogenic effects on macrophages, mast cells, neutrophils, ILC2s, and NK cells, yet can promote pro-inflammatory signalling in acute high-DAMP (damage associated molecular patterns) settings. In adaptive immunity, it generally suppresses Th1 responses and induces CD8+ T cell exhaustion in chronic conditions, while paradoxically enhancing Th1 differentiation during acute viral infections. Aberrant TRPV1-CGRP signalling exacerbates IL-23/IL-17-driven pathology in psoriasis and experimental autoimmune encephalomyelitis, whereas CGRP depletion in severe systemic infections such as sepsis impairs neuro-immune protection. In the tumour microenvironment, tumours hijack sensory nerves to release CGRP, suppressing anti-tumour immunity, and directly stimulating cancer cell growth. This review highlights the potential of repurposing clinically approved anti-CGRP monoclonal antibodies-currently used for migraine-for conditions where elevated or dysregulated CGRP signalling drives pathology, while emphasizing the need for context-aware targeting to preserve physiological homeostasis.