Abstract

Mucosal immunity—the body’s frontline defense, harboring 80% of the body's immune cells—represents a potent yet underexploited avenue for cancer vaccination. Here, we developed an oral biohybrid vaccine platform by integrating tumor antigen-loaded liposomes with fimbriae-enriched bacteria ( Escherichia coli or VNP20009) through bacterial hitchhiking or membrane hybridization. These biohybrids promote mucosal antigen delivery via glycoprotein 2 (GP2)-mediated microfold-cell (M-cell) transcytosis, enhancing antigen cross-presentation and activation of a mucosa-periphery-tumor immune cascade. Bacterial membrane-hybridized vaccines outperform bacteria-hitchhiking counterparts by reconfiguring dendritic cell (DC) subsets within gut-associated lymphoid tissues (GALTs) and triggering C-C chemokine receptor type 7 (CCR7)-dependent immune cell trafficking, thereby propagating mucosal immune activation toward distal tumor microenvironment (TME) reprogramming and tumor control. When combined with PD-1 blockade, this strategy enhances antitumor efficacy by promoting effector cell mobilization and establishing memory against tumor rechallenge. Collectively, these findings position bacteria-derived arsenal biohybrids as a versatile oral vaccine strategy, advancing mucosal immunotherapy for cancer.