Commensal bacterial hybrid nanovesicles improve immune checkpoint therapy in pancreatic cancer through immune and metabolic reprogramming

Harnessing the immunomodulatory ability of the microbiota , such as fecal microbiota transplantation (FMT), has emerged as a promising strategy to improve cancer immunotherapy . However, the lack of standardization in fecal material formulation and safety concerns have hindered clinical application. To overcome these limitations, we developed a high-yielding method by hybridizing bacteria protoplast-derived membrane nanovesicles (PDNVs) from three colon bacteria strains that have been associated with favorable responses to immune checkpoint therapy, including Akkermansia muciniphila , Bifidobacterium longum , and Bifidobacterium breve . The resulting hybrid nanovesicles (HNVs) are composed mainly of cytoplasmic membrane proteins inherited from the originating bacteria but lack pyrogens such as lipopolysaccharide and lipoteichoic acid . Our study demonstrated that HNVs have superior targeting abilities to tumors and peripheral lymphoid organs, leading to greater capability in inducing innate immune activation, dendritic cell maturation and antigen presentation , as well as tumor microenvironment reprogramming. Combined with αPD-1 blockade therapy, HNVs efficiently inhibited the tumor growth in multiple pancreatic cancer mouse models, including Panc02 subcutaneous and liver metastatic models, and orthotopic KPC-Luc pancreatic cancer model. Mechanically, HNVs simultaneously activated the innate arm of immunity and inhibited tumor oxidative phosphorylation (OXPHOS) to reshape the tumor immune microenvironment for improved αPD-1 blockade therapy. Notably, HNVs administration gave rise to similar tumor regression rates to oral transfer of a mixture of live or inactivated bacteria during αPD-1 blockade therapy, but with fewer adverse effects such as diarrhea and colon-intestinal inflammation. Our findings present a stable, cost-effective, and safe alternative to live bacteria for regulating tumor microenvironment for improved cancer immunotherapy.

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