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We investigated the interplay between tumor-infiltrating nociceptors and immune cells in head and neck squamous cell carcinoma (HNSCC) and melanoma. Upon exposure to cancer-derived sEVs, mouse dorsal root ganglion (DRG) neurons secreted increased amounts of substance P, IL-6, and injury-associated neuronal markers. Patient-derived sEVs sensitized DRG neurons to capsaicin, implying enhanced nociceptor responsiveness. Furthermore, nociceptors cultured with sEVs induced an immunosuppressed state in CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Incubation with conditioned medium from cocultures of neurons and cancer cells resulted in increased expression of markers of MDSCs and suppressive function in primary bone marrow cells, and the combination of neuron-conditioned medium and cancer sEVs promoted checkpoint receptor expression on T cells. Together, these findings reveal that nociceptor neurons facilitate CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell exhaustion and bolster MDSC infiltration into HNSCC and melanoma. Consequently, targeting nociceptors may provide a strategy to disrupt detrimental neuroimmune cross-talk in cancer and potentiate antitumor immunity.\n                  <\/jats:p>","DOI":"10.1126\/scisignal.ads7889","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T17:58:08Z","timestamp":1754416688000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":32,"title":["Tumor-infiltrating nociceptor neurons promote immunosuppression"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5562-2670","authenticated-orcid":true,"given":"Anthony C.","family":"Restaino","sequence":"first","affiliation":[{"name":"Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD 57104, USA."},{"name":"Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Ahmadi","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences, Queen\u2019s University, Kingston, ON K7L 3N6, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuany","family":"Eichwald","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences, Queen\u2019s University, Kingston, ON K7L 3N6, Canada."},{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, Solna 171 77, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amin Reza","family":"Nikpoor","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences, Queen\u2019s University, Kingston, ON K7L 3N6, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin","family":"Walz","sequence":"additional","affiliation":[{"name":"Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD 57104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5647-7826","authenticated-orcid":true,"given":"Mohammad","family":"Balood","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences, Queen\u2019s University, Kingston, ON K7L 3N6, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9932-7174","authenticated-orcid":true,"given":"Sebastien","family":"Talbot","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences, Queen\u2019s University, Kingston, ON K7L 3N6, Canada."},{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, Solna 171 77, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2370-8223","authenticated-orcid":true,"given":"Paola D.","family":"Vermeer","sequence":"additional","affiliation":[{"name":"Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD 57104, USA."},{"name":"Department of Surgery, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.68.2.362-372.2004"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoto.2014.141"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-00224-3"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21387"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.11.014"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2022.105774"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2016.166"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.58077"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells13050413"},{"key":"e_1_3_2_11_2","first-page":"13","article-title":"The trigeminal (V) and facial (VII) cranial nerves: Head and face sensation and movement","volume":"7","author":"Sanders R. 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