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bioRxiv · 10.64898/2026.09.07.749862

A stromal metabolic program suppresses NK-cell immunity to drive tumor progression in HER2-low breast cancer

Carter, K.·Ogunlusi, O.·Sarkar, M.·Akanbi, S.·Nguyen, C.·Nekkanti, M.·Agarwal, A.·Fails, D.·Nawaratna, G.·Klemashevich, C.·Cai, J.·Boland, D. J.·Roy Sarkar, T.
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Abstract

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-{gamma} 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 -keto acids (BCKAs). Mechanistically, BCKAs directly suppress NK-cell IFN-{gamma} 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 in vivo, 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.

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Carter, K., Ogunlusi, O., Sarkar, M., Akanbi, S., Nguyen, C., Nekkanti, M., Agarwal, A., Fails, D., Nawaratna, G., Klemashevich, C., Cai, J., Boland, D. J., Roy Sarkar, T.. 2026-09-14. A stromal metabolic program suppresses NK-cell immunity to drive tumor progression in HER2-low breast cancer. https://doi.org/10.64898/2026.09.07.749862

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