{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:24:03Z","timestamp":1787027043890,"version":"build-2736575974"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"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. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression, which limits the availability of targeted therapies and results in poor prognosis. Immune checkpoint blockade (ICB) therapies have emerged as promising treatments by enhancing anti-tumor immunity; however, a substantial proportion of patients with TNBC exhibit primary or acquired resistance. This resistance is largely influenced by the tumor microenvironment (TME). This study uses integrated single-cell and spatial transcriptomics to elucidate key cellular mechanisms of resistance, with particular emphasis on lipid-mediated stromal-immune interactions within the TNBC TME.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This investigation encompassed analysis of single-cell RNA sequencing (scRNA-seq) data from three TNBC datasets and spatial transcriptomic data from 43 TNBC samples. Spatial niches and cell-cell interactions were identified using the Multimodal Intersection Analysis (MIA) algorithm. Experimentally, adipose-derived mesenchymal stem cells (AD-SCs) were co-cultured with MDA-MB-231 TNBC cells to generate lipid-processing CAFs (lpCAFs) and subsequently co-cultured with THP-1 macrophages. Lipid metabolism and M2 polarization of macrophages were assessed using BODIPY staining, Oil Red O, qPCR, flow cytometry and Western blotting techniques.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      ABCA8\n                      <jats:sup>+<\/jats:sup>\n                      lpCAFs and APOE\n                      <jats:sup>+<\/jats:sup>\n                      lipid-associated macrophages (LAMs) exhibited significant enrichment in ICB-resistant TNBC, with co-localization at the immune-stromal junction. lpCAFs facilitated M2 macrophage polarization through lipid metabolism reprogramming, establishing an immunosuppressive TME. High ABCA8 expression demonstrated correlation with enhanced M2 macrophage infiltration, decreased cytotoxic immune cells, and poorer prognosis. Experimental validation demonstrated that lpCAFs increased expression of lipid metabolism and M2 polarization marker in macrophages, substantiating their immunosuppressive function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      ABCA8\n                      <jats:sup>+<\/jats:sup>\n                      lpCAFs and APOE\n                      <jats:sup>+<\/jats:sup>\n                      LAMs contribute to ICB resistance in TNBC through the establishment of an immunosuppressive TME via lipid metabolism reprogramming. Therapeutic intervention targeting the ABCA8-lipid axis presents a promising strategy to enhance ICB efficacy, potentially advancing TNBC treatment outcomes and improving patient survival.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2025.1729275","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T11:56:53Z","timestamp":1769515013000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["ABCA8-positive lipid-metabolic CAFs mediate immunotherapy resistance in TNBC"],"prefix":"10.3389","volume":"15","author":[{"given":"Weidong","family":"Qin","sequence":"first","affiliation":[{"name":"Department of Epidemiology, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, The Fourth Military Medical University","place":["Xi\u2019an, 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