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Leucine-rich repeat-containing protein 15 (LRRC15) is a TGF\u03b2-regulated antigen expressed by cancer cells of mesenchymal origin and cancer-associated fibroblasts (CAFs). In preclinical studies, ablation of TGF\u03b2-driven LRRC15+ CAFs enhances effector functions of CD8+ T cells. However, the pathobiological mechanisms associated with TGF\u03b2\u2019s upregulation of LRRC15 expression in cancer cells remain unclear. Using an integrated approach combining functional compound screening with scRNA-seq, we reveal key genomic features regulating TGF\u03b2\u2019s ability to increase LRRC15 expression on cancer cells. Construction of gene regulatory networks converged our analyses on four key genes (\n                    <jats:italic toggle=\"yes\">MMP2, SPARC, TGF\u03b2R2,<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">WNT5B<\/jats:italic>\n                    ) central to TGF\u03b2-induced LRRC15 pathobiology in cancer cells. Validation of these genes in cell models and their use in predicting immunotherapy responses highlight their potential in refining immunotherapy strategies and personalizing cotreatment options.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2500524123","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:12:31Z","timestamp":1790093551000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Key regulatory elements of the TGF\u03b2\u2013LRRC15 axis predict disease progression and immunotherapy resistance across cancer types"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1869-2557","authenticated-orcid":false,"given":"Michael","family":"Cheng","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/046rm7j60","id-type":"ROR","asserted-by":"publisher"}],"name":"Bioinformatics Interdepartmental Program, University of California Los 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