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

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.

In 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.

The 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.