Harnessing the immunomodulatory capacity of the microbiota, akin to fecal microbiota transplantation (FMT), has emerged as a promising technique to enhance most cancers immunotherapy. Nevertheless, the dearth of standardization in fecal materials formulation and security issues have hindered medical software. To beat these limitations, we developed a high-yielding methodology by hybridizing micro organism protoplast-derived membrane nanovesicles (PDNVs) from three colon micro organism strains which were related to favorable responses to immune checkpoint remedy, together with Akkermansia muciniphila, Bifidobacterium longum, and Bifidobacterium breve. The ensuing hybrid nanovesicles (HNVs) are composed primarily of cytoplasmic membrane proteins inherited from the originating micro organism however lack pyrogens akin to lipopolysaccharide and lipoteichoic acid. Our research demonstrated that HNVs have superior focusing on talents to tumors and peripheral lymphoid organs, resulting in larger functionality in inducing innate immune activation, dendritic cell maturation and antigen presentation, in addition to tumor microenvironment reprogramming. Mixed with ?PD-1 blockade remedy, HNVs effectively inhibited the tumor development in a number of pancreatic most cancers mouse fashions, together with Panc02 subcutaneous and liver metastatic fashions, and orthotopic KPC-Luc pancreatic most cancers mannequin. Mechanically, HNVs concurrently activated the innate arm of immunity and inhibited tumor oxidative phosphorylation (OXPHOS) to reshape the tumor immune microenvironment for improved ?PD-1 blockade remedy. Notably, HNVs administration gave rise to comparable tumor regression charges to oral switch of a mix of dwell or inactivated micro organism throughout ?PD-1 blockade remedy, however with fewer antagonistic results akin to diarrhea and colon-intestinal irritation. Our findings current a secure, cost-effective, and secure different to dwell micro organism for regulating tumor microenvironment for improved most cancers immunotherapy.