{
  "id": 7329422,
  "title": "A stromal metabolic program suppresses NK-cell immunity to drive tumor progression in HER2-low breast cancer",
  "url": "https://urgent.news/2026/09/14/a-stromal-metabolic-program-suppresses-nk-cell-immunity-to-drive",
  "topic": "health",
  "section": "Health & Medicine",
  "published": "2026-09-14T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.09.07.749862v1?rss=1"
  },
  "original_language": "en",
  "account": "Cancer-associated fibroblasts (CAFs) play a significant role in shaping the tumor microenvironment, but their specific impact on innate immunity in HER2-low breast cancer is not well understood. Researchers have now identified an enriched CAF population, characterized by high S100A4 expression, that expands during HER2-low breast tumor progression and creates a metabolically suppressive niche for the cancer. Spatial analysis of human HER2-low tumors shows an increasing accumulation of these S100A4-enriched CAFs and a corresponding decrease in immune cell infiltration, particularly natural killer (NK) cells.\n\nIn an immunocompetent model of HER2-low mammary tumors, the study demonstrates that these S100A4-enriched CAFs not only contribute to tumor initiation and progression but also actively suppress NK-cell cytotoxicity, production of interferon-gamma (IFN-γ), perforin, and granzyme B. By analyzing CAF-conditioned media, researchers uncovered a low-molecular-weight immunosuppressive program that includes enhanced catabolism of branched-chain amino acids (BCAAs) and the accumulation of branched-chain keto acids (BCKAs). These BCKAs directly inhibit NK-cell IFN-γ production. Furthermore, inhibiting the enzyme branched-chain aminotransferase BCAT1 reduces CAF-mediated NK-cell suppression and restores antitumor cytotoxicity. This inhibition also slows down the growth of HER2-low tumors in vivo, but this effect is diminished when NK cells are depleted, highlighting the importance of NK-cell restoration in the antitumor activity.\n\nThe findings reveal a CAF-driven metabolic immune checkpoint in which S100A4-enriched CAFs utilize BCAT1-dependent BCKA production to suppress NK-cell surveillance and promote HER2-low breast tumor progression. By targeting stromal BCAT1, scientists suggest that this could be a potential strategy to break down CAF-mediated immune suppression and reestablish innate antitumor immunity in this specific type of breast cancer.",
  "summary": "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…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 1,
    "also_reported_by": []
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}