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

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.