Sensory neurons drive immune exclusion by stimulating a dense extracellular matrix in the breast cancer tumor microenvironment

作者：Si‐Wei Zhang, Han Wang, Yi Xiao, Luo-Tian Liu, Minhong Shen, Zhuang Wang, Shen Zhao, Xiao-Hong Ding, Ying Wang, Qing-Yuan Zhuang, Jinfei Ni, Zhi-Ming Shao, Yi-Zhou Jiang · 发表于：Cell · 年份：2026 · DOI：10.1016/j.cell.2026.01.001 · 被引用次数：22 · 研究领域：Cancer, Stress, Anesthesia, and Immune Response、Cancer Immunotherapy and Biomarkers、Neuropeptides and Animal Physiology

Innervation is critical in tumor progression. However, the involvement of sensory neurons in the ecosystem of triple-negative breast cancer (TNBC) remains poorly elucidated. Here, we decipher that sensory neurons, the dominant neuron type in the TNBC ecosystem, drive the immune-excluded tumor microenvironment (TME) by stimulating a dense extracellular matrix. Mechanistically, a high concentration of nerve growth factor (NGF) in TME triggers sensory neurons to secrete the neuropeptide calcitonin gene-related peptide (CGRP), thereby activating cancer-associated fibroblasts (CAFs) to secrete collagen. Specifically, CGRP binds to its receptor RAMP1 (receptor activity modifying protein 1), which is expressed mainly on CAFs, and subsequently activates cyclic AMP (cAMP)/protein kinase A (PKA)/cAMP-response element binding protein 1 (CREB1) signaling to increase collagen deposition. Clinically, targeting sensory neurons remodels the disordered TME and synergizes with anti-programmed cell death protein 1 (PD-1) immunotherapy in TNBC. Collectively, our findings reveal a connection between sensory neurons and CAFs that obstructs antitumor immunity in TNBC. The CGRP antagonist rimegepant thus has clinical translational potential as an immuno-sensitizer to augment tumor immunotherapy.