CGRP at the Neuroimmune Interface: Regulator of Host Defense, Tumor Immunity, and Tissue Homeostasis

Sensory neurons act as crucial hubs for host defense, tumor immunity, and tissue homeostasis by detecting environmental cues and fine-tuning immune responses. Across a diversity of tissues, these neurons establish specialized neuroimmune units with resident immune cells, translating local stimuli into coordinated physiological adaptations. Central to this crosstalk is calcitonin gene-related peptide (CGRP). Released by activated sensory neurons, CGRP dynamically governs immune cell function, neurogenic inflammation, and tissue repair. This review synthesizes current evidence establishing CGRP as a master regulator of neuroimmune communication. We dissect its highly context-dependent roles in microbial infections, the tumor microenvironment, and barrier tissues, emphasizing how microbial identity, spatial niches, and concurrent signaling cues dictate its functional outcomes. Mechanistically, we explore the molecular cascades through which diverse cell types decode CGRP signals, focusing on receptor subtype selectivity and cell-specific adaptor switching. Furthermore, we evaluate emerging therapeutic strategies targeting the CGRP axis-ranging from small-molecule modulators to monoclonal antibodies-and their transformative potential for treating immune-mediated conditions, from chronic inflammation to malignancies. Ultimately, we identify critical knowledge gaps, such as the "CGRP receptor code" and neuromicrobial feedback loops, which must be resolved to fully harness the therapeutic promise of this neuroimmune axis.