Killing Tumor Associated Bacteria with Liposomal Silver-Tinidazole Complex Induces Anticancer Cytotoxic T Cells in Response to Bacteria Derived Neoantigens

The Tumor microbiota is a crucial factor that influences the progression and therapeutic outcome of cancer. We report that pre-resection antibiotics targeting anaerobic bacteria significantly improved the disease-free survival rate of colorectal cancer (CRC) patients by 25%. We designed an antibiotic silver-tinidazole complex encapsulated in liposomes (LipoAgTNZ) to eliminate tumor-associated bacteria in the primary tumor and liver metastasis without causing gut microbiome dysbiosis. Murine CRC models colonized by tumor-promoting bacteria (Fusobacterium nucleatum spp), or probiotics (Escherichia coli Nissle spp) responded to LipoAgTNZ therapy, which enabled > 70% long-term survival in two F. nucleatum infected CRC models. The antibiotic treatment elicited antitumor efficacy of CD8+ T cells by yielding microbial sources of neoantigens. Both heterologous and homologous bacterial epitopes contributed to the immunogenicity, by which T cells were primed to recognize both the infected and uninfected tumors. Our strategy targets tumor-associated bacteria to elicit antitumoral immunity paving the way for microbiome-immunotherapy interventions.The whole exome sequencing data for CT26FL3 (RFP/Luc) cells supplement the manuscript.