伤害感受器神经元抑制乳腺癌中的抗肿瘤免疫

Peripheral nerves are emerging regulators of the tumor microenvironment, but how sensory innervation shapes breast cancer immunity remains poorly defined.

Here we show that triple-negative breast cancers (TNBCs) co-opt nociceptor neurons to suppress antitumor immunity and promote disease progression. Across orthotopic TNBC models, we found that primary tumors and tumor-draining lymph nodes were densely innervated by CGRP + sensory fibers. Tumor-derived cues directly activated dorsal root ganglion neurons, increased calcium responsiveness, induced Ngfr and Atf3, and triggered release of CGRP and substance P.

Mechanistically, a tumor-derived proNGF-NGFR axis reprogrammed nociceptors and promoted neuropeptide secretion. Soluble mediators from activated nociceptors suppressed CD8 + T cell-mediated tumor-cell killing, whereas sensory-neuron silencing or ablation curtailed tumor growth and remodeled the immune microenvironment toward dendritic-cell activation, myeloid reprogramming, and enhanced CD8 + T cell and NK-cell effector states.

Subset-specific analysis revealed nonredundant sensory control of immune states, with MrgD + neurons selectively shaping macrophage-centered programs.

Finally, blockade of CGRP signaling through RAMP1 reduced tumor growth and markedly enhanced PD-1 blockade, nearly eliminating primary tumor burden and lung metastasis in vivo. T cell-specific Ramp1 deletion similarly restrained tumor growth, and RAMP1 + CD8 + T cells in human TNBC displayed an exhaustion-associated phenotype.

Together, these findings define a tumor-promoting proNGF-nociceptor-CGRP-RAMP1 axis and identify neuroimmune signaling as a therapeutically actionable vulnerability in TNBC.