We found that the cancerous pancreas harbors a markedly more abundant microbiome compared to normal pancreas in both mice and humans, while select bacteria are differentially increased in the tumorous pancreas compared to gut. Ablation of the microbiome protects against pre-invasive and invasive PDA, whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor-protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting Th1 differentiation of CD4+ T cells and CD8+ T cell activation. Bacterial ablation also enabled efficacy for checkpoint-targeted immunotherapy by upregulating PD-1 expression. Mechanistically, the PDA microbiome generated a tolerogenic immune program by differentially activating select toll-like receptors in monocytic cells. These data suggest that endogenous microbiota promote the crippling immunesuppression characteristic of PDA and that the microbiome has potential as a therapeutic target in the modulation of disease progression.