{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T21:20:47Z","timestamp":1778620847499,"version":"3.51.4"},"posted":{"date-parts":[[2026,5,10]]},"group-title":"Cancer Biology","reference-count":145,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T00:00:00Z","timestamp":1778371200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"American Society of Clinical Oncology Conquer Cancer Foundation Young Investigator Award"},{"name":"The Ohio State University Comprehensive Cancer Center"},{"name":"the International Kidney Cancer Coalition Cecile and Ken Youner Scholarship"},{"name":"the Society for Immunotherapy of Cancer-NanoString Technologies Single Cell Biology Award"},{"name":"the Kidney Cancer Association Young Investigator Award"},{"name":"Gateway Cancer Research Foundation"},{"name":"the Pelotonia Institute for Immuno-Oncology"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Brain metastasis (BM) in renal cell carcinoma (RCC) remains poorly understood and often resistant to immune checkpoint inhibitors. We generated a large single-nucleus RNA-seq data of RCC BM, profiling 14 BM samples alongside matched extracranial metastases and primary tumors. Tumor cells in BM displayed neuronal infiltration, neural-like adaptation, and marked remodeling of the microenvironment, including expansion of immunosuppressive myeloid cells and depletion of antigen-presenting dendritic cells. Tumor, immune, and stromal cells exhibited metabolic rewiring characterized by fatty-acid metabolism, oxidative phosphorylation, and MYC-driven programs. CD8\u207a T cells showed terminal exhaustion and impaired proliferative capacity, and tertiary lymphoid structures were absent. Spatial profiling of 12 BM samples (13,128 cells) validated key cellular interactions, while ligand\u2013receptor analysis revealed immunoregulatory circuits between tumor, stromal, and immune cells. These findings define BM-specific adaptations that promote immune evasion and resistance, revealing therapeutic vulnerabilities in RCC BM.<\/jats:p>\n                <jats:sec>\n                  <jats:title>SIGNIFICANCE<\/jats:title>\n                  <jats:p>Single-nucleus RNA-sequencing profiling reveals tumor, immune, and metabolic adaptations in renal cell carcinoma (RCC) brain metastases, including neuroglial remodelling and immunosuppressive niche formation. These findings identify immune evasion mechanisms that could contribute to therapeutic resistance, providing new avenues for site-specific therapeutic interventions to improve treatment efficacy and outcomes in patients with RCC BM.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.06.722652","type":"posted-content","created":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T16:05:12Z","timestamp":1778429112000},"source":"Crossref","is-referenced-by-count":0,"title":["Single-Cell Atlas of Renal Cell Carcinoma Brain Metastasis Uncovers Mechanisms of Immune Dysfunction and Resistance"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8914-2358","authenticated-orcid":false,"given":"Mostafa I.H.","family":"Ali","sequence":"first","affiliation":[{"name":"Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA"},{"name":"Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeynep Feyza","family":"Akpinar","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA"},{"name":"Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose A","family":"Ovando-Ricardez","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA"},{"name":"Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna K.","family":"Casasent","sequence":"additional","affiliation":[{"name":"Department of Hematopoietic Biology & Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Truong Nguyen","family":"Anh Lam","sequence":"additional","affiliation":[{"name":"Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jerome","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Narmina","family":"Khanmammadova","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA"},{"name":"Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick K.","family":"Reville","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology\/Oncology, Nuvance Health, Norwalk, CT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J. H.","family":"Shih","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adeboye O.","family":"Osunkoya","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Urology, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa M.","family":"Norberg","sequence":"additional","affiliation":[{"name":"Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tuan M.","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianzhuo","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anh G.","family":"Hoang","sequence":"additional","affiliation":[{"name":"Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sahin","family":"Hanalioglu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Hacettepe University Faculty of Medicine, Ankara, Turkey"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mehmet Asim","family":"Bilen","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frederick","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason T.","family":"Huse","sequence":"additional","affiliation":[{"name":"Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Navin","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Division of Discovery Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Merve","family":"Hasanov","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA"},{"name":"Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Jonasch","sequence":"additional","affiliation":[{"name":"Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7195-0842","authenticated-orcid":false,"given":"Elshad","family":"Hasanov","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA"},{"name":"Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026051213501544000_2026.05.06.722652v1.1","first-page":"10","article-title":"Cancer statistics, 2025. 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