Microbiota-Derived L-SeMet Potentiates CD8+ T Cell Effector Functions and Facilitates Anti-Tumor Responses

Extensive studies have shown that gut microbiota-derived metabolites can enhance the antitumor efficacy of immunotherapy by modulating host immune responses. However, the more comprehensive spectrum of such metabolites and their mechanisms remain unclear. In this study, we demonstrated that L-selenomethionine (L-SeMet), a gut microbial metabolite, acts as a positive regulator of immunotherapy. Through screening of a repository of gut microbial metabolites, we identified that L-SeMet can effectively enhance the effector function of CD8⁺ T cells. Furthermore, intragastric administration of L-SeMet in mice significantly suppressed the growth of subcutaneous MC38 tumors. Mechanistically, L-SeMet enhances T cell receptor (TCR) signaling by promoting LCK phosphorylation. Collectively, our findings reveal that the gut microbial metabolite L-SeMet inhibits colorectal tumor growth by potentiating CD8⁺ T cell functions, providing a potential therapeutic strategy for colorectal cancer treatment.