Quercetin targets BCAT1 to potentiate CD8+ T cell immunity by rewiring branched-chain amino acid metabolism against colorectal cancer metastasis.

Colorectal cancer (CRC) metastasis is a major cause of cancer‑related death, highlighting the need for therapies that target immune‑metabolic pathways. Here, we show that quercetin inhibits CRC progression via dual actions: directly suppressing tumor cell growth and migration, while systemically reinvigorating CD8+ T cell mediated immunity. In vitro, quercetin potently inhibited CRC cell proliferation, migration, and survival. In an experimental lung metastasis mouse model, quercetin enhanced the effector function of CD8+ T cells, as evidenced by increased production of Granzyme B, Perforin, and IFN-γ in metastases, blood, and tumor-draining lymph nodes. Metabolomic profiling uncovered a pronounced remodeling of branched-chain amino acid (BCAA) metabolism following quercetin intervention. Screening via the HERB database identified BCAA transaminase 1 (BCAT1) as a candidate target, confirmed by molecular docking and surface plasmon resonance (SPR). Importantly, the combination of oral leucine and quercetin produced a synergistic effect, significantly boosting CD8+ T cell cytotoxicity and dramatically reducing the lung metastatic burden. Taken together, these data identify BCAT1 as a direct target of quercetin and elucidate a resultant immunometabolic circuit that bolsters CD8+ T cell function, providing a rationale for targeting this pathway in advanced CRC.