{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T06:10:23Z","timestamp":1791526223667,"version":"4.3.4"},"reference-count":156,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Therapeutic resistance remains the principal cause of mortality in breast cancer. While the tumor microenvironment (TME) is a key contributor, therapies targeting isolated TME components, whether immune, metabolic, or spatial, have largely failed due to compensatory adaptations and ecological resilience. This review synthesizes recent advances to propose a tripartite \u201cImmune-Metabolic-Spatial\u201d axis as the fundamental organizer of a robust resistance niche. We elucidate how immunosuppressive cells, such as TAMs and Tregs, are metabolically sustained by altered nutrient availability like lactate and hypoxia, while spatial constraints, including CAF-deposited ECM and DDR1-mediated collagen alignment, physically impede drug delivery and immune infiltration. Critically, we highlight reciprocal crosstalk where metabolic reprogramming dictates immune cell function, in turn influencing stromal remodeling to create a self-reinforcing resistance loop. Beyond mechanism, we evaluate emerging strategies that concurrently target multiple axes, such as combining immune checkpoint blockade with metabolic inhibitors or stromal disruptors. Finally, we discuss clinical translation through biomarker development and innovative trial designs, framing the tripartite axis as an actionable framework for overcoming therapeutic resistance.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1748257","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T06:43:37Z","timestamp":1774248217000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting the tripartite axis of immune-metabolic-spatial crosstalk to overcome therapy resistance in breast cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Siyu","family":"He","sequence":"first","affiliation":[{"name":"Department of Pathology, Shengjing Hospital of China Medical University","place":["Shenyang, Liaoning, China"]},{"name":"Key Laboratory of Intelligent and Precision Pathology Diagnosis in Oncology, China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuyan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Liaoning Health Industry Group Bengang General Hospital","place":["Benxi, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingjie","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Pathology, Shengjing Hospital of China Medical University","place":["Shenyang, Liaoning, China"]},{"name":"Key Laboratory of Intelligent and Precision Pathology Diagnosis in Oncology, China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.actbio.2025.08.054","article-title":"Advances in photodynamic therapy and its combination strategies for breast 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