Abstract
The gut microbiota represents a promising target to enhance cancer immunotherapy, yet the microbial molecules mediating anti-tumor immunity remain poorly defined. Here, we identify a human-derived strain, Lactobacillus fermentum MI37, that augments anti-tumor immune responses and synergizes with anti-PD-1 therapy. MI37 induces robust IFN-γ production with minimal IL-10, increases tumor-infiltrating cytotoxic T lymphocytes, and upregulates inflammatory gene programs in a syngeneic mouse model. Notably, heat-killed MI37 retains its immunostimulatory and anti-tumor effects, indicating a structural microbial component mediates activity. Fractionation identifies lipoteichoic acid (LTA) as the key effector and purified Staphylococcus aureus-derived LTA recapitulates MI37-induced IFN-γ production and CD8(+) T cell activation. Genomic and proteomic analyses further reveal MI37-specific features in teichoic acid biosynthesis, including a distinctive sulfatase N-terminal domain-containing LTA synthase. These findings establish LTA-producing probiotics as potential microbial adjuvants to improve cancer immunotherapy efficacy.