A systematic pan-cancer analysis of intratumoral microbiota-derived epitopes to inform cancer immunotherapy and prevention

Intratumoral microbial antigens, which mimic tumor antigens, can be presented by human leukocyte antigen (HLA) molecules, thereby eliciting antitumor immune responses. However, a comprehensive pan-cancer characterization of such molecularly mimicking microbial epitopes is still lacking. Here, we construct a pan-cancer microbial epitope landscape from 1190 samples across 24 cancer types. Pan-cancer analyses reveal that microbial epitopes exhibit higher hydrophobicity, aliphatic indices, and stability than human epitopes. Nine HLA-I alleles tend to bind microbial epitopes, and HLA-C alleles show a stronger tendency to present microbial epitopes than HLA-A and HLA-B alleles. Moreover, we reveal that microbial species capable of generating HLA-I epitopes are more prevalent in tumors, that broadly detected epitopes span more cancer types, and that multiple microbial genera generate numerous immunogenic epitopes. Notably, homologous microbial epitopes and tumor antigens elicit cross-reactive T cell responses, and experimental evidence demonstrates that microbial epitopes exhibit enhanced immunogenicity and antitumor efficacy. Overall, our findings provide a foundation for microbial epitope vaccine development, offering insights for cancer prevention and therapy.