{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T20:02:13Z","timestamp":1789761733113,"version":"4.0.1"},"posted":{"date-parts":[[2026,9,14]]},"group-title":"Cancer Biology","reference-count":73,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Cancer-associated fibroblasts (CAFs) are major regulators of the tumor microenvironment, yet how distinct CAF states suppress innate immunity in HER2-low breast cancer remains poorly understood. Here, we identify an S100A4-enriched CAF population that expands during HER2-low breast tumor progression and establishes a metabolically immunosuppressive niche. Spatial transcriptomics and multiplex imaging of human HER2-low tumors reveal progressive CAF accumulation and an inverse spatial association between S100A4-enriched CAFs and immune infiltration, including natural killer (NK) cells. Using an immunocompetent HER2-low mammary tumor model, we show that S100A4-enriched CAFs promote tumor initiation and progression while suppressing NK-cell cytotoxicity, IFN-\u03b3 production, perforin, and granzyme B. Fractionation of CAF-conditioned media and metabolic profiling identify a low-molecular-weight immunosuppressive program characterized by enhanced branched-chain amino acid catabolism and accumulation of branched-chain \u03b1-keto acids (BCKAs). Mechanistically, BCKAs directly suppress NK-cell IFN-\u03b3 production, whereas inhibition of the branched-chain aminotransferase BCAT1 reduces CAF-mediated NK-cell suppression and restores antitumor cytotoxicity. BCAT1 inhibition also suppresses HER2-low tumor growth\n                  <jats:italic>in vivo<\/jats:italic>\n                  , an effect attenuated by NK-cell depletion, establishing NK-cell restoration as a functional component of its antitumor activity. Together, these findings uncover a CAF-driven metabolic immune checkpoint in which S100A4-enriched CAFs exploit BCAT1-dependent BCKA production to suppress NK-cell surveillance and promote HER2-low breast tumor progression. Targeting stromal BCAT1 therefore represents a potential strategy to dismantle CAF-mediated immune suppression and restore innate antitumor immunity.\n                <\/jats:p>","DOI":"10.64898\/2026.09.07.749862","type":"posted-content","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T17:20:37Z","timestamp":1789406437000},"source":"Crossref","is-referenced-by-count":0,"title":["A stromal metabolic program suppresses NK-cell immunity to drive tumor progression in HER2-low breast cancer"],"prefix":"10.64898","author":[{"given":"Kayla","family":"Carter","sequence":"first","affiliation":[{"name":"Department of Biology, Texas A&M University, College Station, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olajumoke","family":"Ogunlusi","sequence":"additional","affiliation":[{"name":"Department of Biology, Texas A&M University, College Station, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mrinmoy","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Department of Biology, Texas A&M University, College Station, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Akanbi","sequence":"additional","affiliation":[{"name":"Department of Biology, Texas A&M University, College Station, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Biology, Texas A&M University, College Station, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manasa","family":"Nekkanti","sequence":"additional","affiliation":[{"name":"Department of Biology, Texas A&M University, College Station, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akash","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Department of Biology, Texas A&M University, College Station, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Fails","sequence":"additional","affiliation":[{"name":"Fortis Life Sciences, Montgomery, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gayan I.","family":"Nawaratna","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cory","family":"Klemashevich","sequence":"additional","affiliation":[{"name":"Integrated Metabolomics Analysis Core, Texas A&M University, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8081-6725","authenticated-orcid":false,"given":"James","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Veterinary Integrative Biosciences, Texas A&M University, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devon J.","family":"Boland","sequence":"additional","affiliation":[{"name":"Texas A&M Institute of Genome Sciences & Society (TIGSS), College Station, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8556-3026","authenticated-orcid":false,"given":"Tapasree","family":"Roy Sarkar","sequence":"additional","affiliation":[{"name":"Department of Biology, Texas A&M University, College Station, TX, USA"},{"name":"Texas A&M Center for Biological Clocks Research, College Station. 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