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Patients with SWN overwhelmingly present with intractable chronic pain. There are no FDA\u2010approved drugs to halt tumor growth or alleviate pain. Research on SWN is hindered by the lack of clinically relevant models. We established patient\u2010derived SWN cell lines from patients with varying pain levels and developed orthotopic patient\u2010derived xenograft models that reproduce patients\u2019 pain responses. We further developed a novel dorsal root ganglia (DRG) imaging model for longitudinal intravital imaging of macrophage infiltration into the DRG and sensory neuron pain response. Leveraging these novel models, we found that Schwannomas grown distantly in the peripheral nerve caused an influx of macrophages into the DRG. These macrophages in the DRG caused pain via overproducing\u00a0IL\u20106. Treatment with anti\u2010IL\u20106 antibody reduced pain but had modest efficacy in tumor control. We identified epidermal growth factor receptor (EGFR) signaling as a key driver of schwannoma growth and an escape mechanism from anti\u2010IL6 treatment. Finally, we found that combining IL\u20106 and EGFR blockade effectively controlled pain and tumor growth simultaneously in SWN models. In summary, we elucidated the cellular and molecular crosstalk between schwannoma (HMGB1), neuron (CCL2), and macrophage (IL\u20106) in driving pain, and identified the EGF signaling pathway as a driver of SWN tumor progression, thereby uncovering novel therapeutic targets that may improve clinical management of SWN.<\/jats:p>","DOI":"10.1002\/advs.202515597","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T20:51:07Z","timestamp":1773003067000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Deciphering and Targeting the Schwannoma\u2010Neuron\u2010Macrophage Crosstalk for the Treatment of Schwannomatosis and Associated Pain"],"prefix":"10.1002","volume":"13","author":[{"given":"Zhenzhen","family":"Yin","sequence":"first","affiliation":[{"name":"Edwin L. 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Steele Laboratories Department of Radiation Oncology Massachusetts General Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute for Innovation in Imaging Center for Systems Biology and Division of Neuroradiology Department of Radiology Massachusetts General Hospital  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonu","family":"Subudhi","sequence":"additional","affiliation":[{"name":"Edwin L. Steele Laboratories Department of Radiation Oncology Massachusetts General Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Ho","sequence":"additional","affiliation":[{"name":"Edwin L. Steele Laboratories Department of Radiation Oncology Massachusetts General Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Edwin L. Steele Laboratories Department of Radiation Oncology Massachusetts General Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Ren","sequence":"additional","affiliation":[{"name":"Edwin L. Steele Laboratories Department of Radiation Oncology Massachusetts General Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gino B.","family":"Ferraro","sequence":"additional","affiliation":[{"name":"Edwin L. 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