Self-lytic Nano-bacterial biohybrid reprograms Intratumoral microbiome-immune interactions for cancer immunotherapy

Despite significant advances in cancer immunotherapy, therapeutic outcomes remain limited by the dynamic interactions between the microbiome and immune cells in the tumor microenvironment (TME). In particular, Fusobacterium nucleatum (Fn) poses a significant barrier by suppressing the function of immune cells, such as natural killer (NK) cells. Here, we developed a nano-bacterial biohybrid system, LYC@Bac, which integrates IL-15-expressing probiotics (Bac) and pH-sensitive lysozyme nanoparticles (LYC). This system targets the microbiome and immune cells in the TME through simultaneous elimination of Fn and activation of NK cells, thereby potentiating cancer immunotherapy. Briefly, the acidic TME triggers lysozyme release via pH-labile imine bonds, lysing Fn to alleviate immunosuppression and releasing PAMPs that activate dendritic cells. Concurrently, Bac lysed by lysozyme releases IL-15, which subsequently activates the mTOR pathway in NK cells, upregulating NKG2D expression and enhancing granzyme and perforin secretion. This process augments the antitumor immunity of NK cells while concurrently enhancing their antibacterial function, leading to intensified clearance of Fn and further alleviation of immunosuppression, thereby creating a positive feedback loop. The LYC@Bac biohybrid offers a precise strategy to modulate intratumoral microbiome-immune cell interactions, providing a promising approach for enhanced cancer immunotherapy.