This research investigates how perineural invasion (PNI) serves as a critical driver of treatment resistance in triple-negative breast cancer (TNBC). The studies reveal that sensory neurons within the tumor microenvironment release a signaling molecule called CGRP, which interacts with fibroblasts to promote excessive collagen deposition. This structural reorganization creates a physical barrier that prevents immune cells from attacking the tumor, thereby shielding the cancer from immunotherapy. Clinical data from multiple cohorts confirm that higher nerve density correlates with poorer survival and increased metastasis. To combat this, the authors suggest that using CGRP inhibitors—originally designed for migraines—can dismantle this barrier. When combined with anti-PD-1 therapy, these inhibitors successfully restore immune infiltration and significantly improve the efficacy of cancer treatments in experimental models.

References:

• Zhang S W, Wang H, Xiao Y, et al. Sensory neurons drive immune exclusion by stimulating a dense extracellular matrix in the breast cancer tumor microenvironment[J]. Cell, 2026.