Enterococcus peptidoglycan remodeling promotes checkpoint inhibitor immunotherapy

The antitumor efficacy of cancer immunotherapy can correlate with the presence of certain bacterial species within the gut microbiome, and yet many of the molecular mechanisms that impact host response to immunotherapy remain elusive. Here, we show that members of the bacterial genus Enterococcus modulate response to checkpoint inhibitor immunotherapy in mouse tumor models. Active enterococci express and secrete orthologs of the NlpC/p60 peptidoglycan hydrolase SagA that generate immune-active muropeptides. Expression of SagA in non-protective E. faecalis was sufficient to promote anti-PD-L1 response, and its activity required the peptidoglycan sensor Nod2. Notably, SagA-engineered probiotics or synthetic muropeptides also augmented anti-PD-L1 efficacy. Together, our data suggest that microbiota species with unique peptidoglycan remodeling activity and muropeptide-based therapeutics may enhance cancer immunotherapy and could be leveraged as next-generation adjuvants.