Tumor-resident Lactobacillus iners confers chemoradiation resistance through lactate-induced metabolic rewiring

Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in cervical cancer patients through a combined approach of deep microbiome sequencing, sequential, targeted bacterial culture and in vitro assays. We identify that an obligate L-lactate producing lactic acid bacteria found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemotherapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring of tumors. Genomically similar L-lactate producing lactic acid bacteria commensal to other body sites are also significantly associated with survival in colorectal cancer, lung cancer, head and neck cancer and skin cancer. Our findings demonstrate that lactic acid bacteria in the tumor microenvironment can alter tumor metabolism and lactate signaling pathways to cause therapy resistance. Lactic acid bacteria could be promising therapeutic targets across cancer types.