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Nociceptor neurons suppress antitumor immunity in breast cancer

ABSTRACT: Peripheral nerves are emerging regulators of the tumor microenvironment, but how sensory innervation shapes breastcancer immunity remains poorly defined. Here we show that triple-negative breast cancers (TNBCs) co-opt nociceptorneurons to suppress antitumor immunity and promote disease progression. Across orthotopic TNBC models, we foundthat primary tumors and tumor-draining lymph nodes were densely innervated by CGRP⁺ sensory fibers. Tumor-derivedcues directly activated dorsal root ganglion neurons, increased calcium responsiveness, induced Ngfr and Atf3, andtriggered release of CGRP and substance P. Mechanistically, a tumor-derived proNGF-NGFR axis reprogrammednociceptors and promoted neuropeptide secretion. Soluble mediators from activated nociceptors suppressed CD8⁺ Tcell-mediated tumor-cell killing, whereas sensory-neuron silencing or ablation curtailed tumor growth and remodeled theimmune 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 lungmetastasis in vivo. T cell-specific Ramp1 deletion similarly restrained tumor growth, and RAMP1⁺ CD8⁺ T cells in humanTNBC displayed an exhaustion-associated phenotype. Together, these findings define a tumor-promoting proNGF-nociceptor-CGRP-RAMP1 axis and identify neuroimmune signaling as a therapeuticall

ORGANISM(S): Mus musculus

PROVIDER: GSE336080 | GEO | 2026/08/22

REPOSITORIES: GEO

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