Talbot, Sebastien, Wu, Yue, Ahmadi, Maryam, Bogoslowski, Ania, Brabenec, Laura, Abbadi, Jumana, Rocha, Beatriz, Nikpoor, Amin Reza, Thiel, Vera, Preto, Elisa, Sulaiman, Sheu, Tsamchoe, Migmar, Dory, Alissa, McIlvried, Lisa, Eichwald, Tuany, McErlain, Tamara, Balood, Mohammad, Boutopoulos, Christos, Rafei, Moutih, Vermeer, Paola, Chang, Aeson, Sloan, Erica, Amit, Moran, Penninger, Josef, Saragovi, Uri, Trumpp, Andreas, Scheff, Nicole, Dixon, Karen, Cox, Maureen, Birbrair, Alexander, Borniger, Jeremy C, Bednova, Olga (June 2026) Nociceptor neurons suppress antitumor immunity in breast cancer. Research Square. (Submitted)
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Abstract
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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > breast cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Borniger lab CSHL Post Doctoral Fellows |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 9 June 2026 |
| Date Deposited: | 01 Jul 2026 13:11 |
| Last Modified: | 01 Jul 2026 13:11 |
| PMCID: | PMC13278325 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/42250 |
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