{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:55:49Z","timestamp":1791327349114,"version":"4.3.1"},"reference-count":91,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    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 \u201cdouble agent,\u201d 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\n                    <jats:sup>+<\/jats:sup>\n                    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\u2014currently used for migraine\u2014for conditions where elevated or dysregulated CGRP signalling drives pathology, while emphasizing the need for context-aware targeting to preserve physiological homeostasis.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1841366","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T04:43:18Z","timestamp":1783485798000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["CGRP: the immune system\u2019s double agent \u2013 context-dependent roles in inflammation, resolution and cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Mushref Bakri","family":"Assas","sequence":"first","affiliation":[{"name":"Faculty of Applied Medical Sciences, Department of Medical Laboratory Technology, Immunology Group, King Abdul Aziz University","place":["Jeddah, Saudi Arabia"]},{"name":"EcoHealth Unit, King Fahd Medical Research Centre, King Abdulaziz University","place":["Jeddah, Saudi Arabia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1335387","article-title":"From pain to tumor immunity: influence of peripheral sensory neurons in cancer","volume":"15","author":"Mardelle","year":"2024","journal-title":"Front Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2014.00023","article-title":"Calcitonin gene-related peptide is a key neurotransmitter in the neuro-immune axis","volume":"8","author":"Assas","year":"2014","journal-title":"Front Neurosci"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0147-2","article-title":"Pain and immunity: implications for host defence","volume":"19","author":"Baral","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1080\/14728222.2020.1724285","article-title":"Calcitonin gene-related peptide (CGRP): role in migraine pathophysiology and therapeutic targeting","volume":"24","author":"Wattiez","year":"2020","journal-title":"Expert Opin Ther Targets"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/jcm13185616","article-title":"Comparison between substance P and calcitonin gene-related peptide and their receptors in colorectal adenocarcinoma","volume":"13","author":"Serban","year":"2024","journal-title":"J Clin Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2000.tb05397.x","article-title":"Nerve-driven immunity. 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