Klebsiella pneumoniae LPS drives stromal-mediated repression of p53 and colorectal cancer chemoresistance.

The gut bacterial microbiota is increasingly recognized as a key modulator of colorectal cancer (CRC) initiation, progression and response to therapy. However, the mechanisms by which bacteria influence the response to anticancer drugs remain poorly understood. Here, we investigate the effects of microbiota-driven signaling on the tumor suppressor p53 and its impact on chemotherapy. We uncover a mechanism by which lipopolysaccharide (LPS) from Klebsiella pneumoniae and other Enterobacteria impairs p53 activity and promotes chemoresistance via paracrine signaling from the tumor microenvironment. While direct exposure to LPS did not alter the drug response of CRC cells, conditioned media from LPS-stimulated macrophages or fibroblasts suppressed p53 accumulation and attenuated the response to chemotherapeutic agents. Deep quantitative proteomics further revealed selective inhibition of a subset of p53 targets by inflammation. This same subset negatively correlated with inflammatory signature and immune infiltration in patients and was associated with improved survival following chemotherapy. Mechanistically, our data suggest that macrophage-derived extracellular vesicles contribute to p53 degradation in cancer cells. Overall, our findings reveal a microbiota-driven mechanism of p53 suppression via the microenvironment that contributes to chemoresistance, highlighting the impact of bacteria on tumor cell fate and therapeutic efficacy in CRC.