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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,2,10]]},"abstract":"<jats:p>Estrogen receptor (ER) positive breast cancer is the most prevalent subtype, commonly responsive to endocrine therapies. Immune checkpoint inhibitors (ICIs) have limited efficacy in ER-positive disease, highlighting the need for the development of combination immunotherapies for these patients. We previously established that nitroso-N-methylurea-induced mammary tumors in outbred Sprague-Dawley rats mimic immune evasive mechanisms and the heterogeneity of ICI response observed in patients. We identified a \u201cluminal growing\u201d gene signature in ER-positive tumors, which correlated with tumor growth and immune-related differences. Here, we evaluated targeting candidates from this signature KMT5B\/C and IKBKE using inhibitors A-196 and IKBKEi respectively, alongside anti-estrogen (fulvestrant) and a TGF\u03b2 blocking antibody (NIS793), both individually and in combination with \u03b1PD-L1, within this rat model. Fulvestrant emerged as the most effective treatment, inducing regression of most existing tumors and reducing on-treatment tumor burden when combined with \u03b1PD-L1. A-196, while ineffective as a monotherapy, demonstrated enhanced response when combined with \u03b1PD-L1. Comprehensive tumor profiling through polychromatic flow cytometry and single-cell RNA sequencing revealed that A-196 induced a luminal-to-basal shift in tumor epithelial cells, enhancing antigen presentation, whereas epithelial-to-mesenchymal transition was linked to fulvestrant resistance. Our findings underscore the value of the rat mammary tumor model for preclinical studies in ER-positive breast cancer and advocate for the further validation and potential clinical development of KMT5B\/C inhibitors to enhance the efficacy and broaden the applicability of ICI therapy in cancer patients.<\/jats:p>","DOI":"10.1073\/pnas.2501052123","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T19:09:38Z","timestamp":1770318578000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["Evaluation of targeted and immune combination therapies in a rat model of hormone receptor\u2013positive breast cancer"],"prefix":"10.1073","volume":"123","author":[{"given":"Ernesto","family":"Rojas-Jimenez","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute","place":["Boston"]},{"name":"Department of Medicine, Brigham and Women\u2019s 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Rojas Single-cell RNA sequencing of rat mammary tumors treated with epigenetic and endocrine therapies. NCBI Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE284698. 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