Microbiota-indole-3-propionic acid-heart axis mediates the protection of leflunomide against αPD1-induced cardiotoxicity in mice

Anti-programmed death 1 (αPD1) immune checkpoint blockade is used in combination for cancer treatment but associated with cardiovascular toxicity. Finding drugs that suppress cardiovascular toxicity but not compromise the efficacy of αPD1-mediated immunotherapy is of great importance. Leflunomide (Lef) can suppress the growth of several tumor and mitigate cardiac remodeling in mice. However, the specific role of Lef in αPD1-induced cardiotoxicity remains unclear. Using a novel melanoma mouse model, we assessed the protective effect of Lef on αPD1-induced cardiotoxicity. Fecal microbiota transplantation (FMT), 16S rRNA gene sequencing, metabolomics analysis and RNA sequencing were performed to reveal the underlying mechanisms.