Sensory Neurons Drive a Fibrotic Immune Microenvironment in Breast Cancer

Triple-negative breast cancer (TNBC) is the most aggressive and treatment-refractory breast cancer subtype. Although immune checkpoint blockade (ICB) has shown promise, only a subset of patients achieve durable responses. Resistance to immunotherapy is often linked to an immunosuppressive tumor microenvironment (TME). Emerging evidence suggests that the nervous system plays a role in regulating tumor progression and antitumor immunity; however, how perineural invasion (PNI) influences the breast cancer TME remains poorly understood. Zhang, Wang, Xiao, Liu, and colleagues demonstrate that sensory neurons are key drivers of immune exclusion in TNBC by activating cancer-associated fibroblasts (CAF) and promoting a collagen-rich, desmoplastic TME. In mouse models, sensory neuron activation via a low-dose capsaicin diet accelerated tumor growth, expanded CAF populations, and suppressed immune infiltration. In contrast, genetic or chemical ablation of sensory neurons restored an immune-permissive TME, reduced fibrosis, and slowed tumor progression. Mechanistically, tumor cell–derived nerve growth factor (NGF) activated sensory neurons, enhancing neurite outgrowth and secretion of calcitonin gene-related peptide (CGRP). Ngf knockdown diminished neuronal activation and suppressed tumor growth. Neuron-derived CGRP reprogrammed CAFs toward a myofibroblastic CAF phenotype via RAMP1–cAMP–PKA–CREB1 signaling, driving collagen deposition and immune exclusion. The resulting dense extracellular matrix likely limited immune cell infiltration and contributed to the immune-cold TME observed in PNI-positive tumors. Pharmacologic or genetic disruption of CGRP–RAMP1–CREB1 signaling reduced desmoplasia, restored CD8+ T-cell infiltration, and inhibited tumor growth. Importantly, combined targeting of sensory neurons or CGRP with anti–PD-1 therapy produced synergistic antitumor effects. Clinically, high CGRP expression correlates with poor prognosis and reduced immunotherapy responsiveness, highlighting CGRP as a predictive biomarker and potential therapeutic target. These findings establish sensory neurons as central drivers of stromal remodeling and immune exclusion in TNBC and suggest that repurposing approved CGRP inhibitors such as rimegepant could enhance immunotherapy outcomes in immunotherapy-resistant disease.Zhang S-W, Wang H, Xiao Y, Liu L-T, Shen M, Wang Z, et al. Sensory neurons drive immune exclusion by stimulating a dense extracellular matrix in the breast cancer tumor microenvironment. Cell 2026 Feb 5 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.