Precision tumor immunotherapy via a dual-gated macrophage-bacterial activation platform

Immunotherapy based on live microorganisms has shown promise in preclinical studies, but its clinical translation has been hampered by limited efficacy and non-negligible toxicity. Here, we developed Macrophage-Bacteria encapsulation Lytic Autoactivated Synergistic Therapeutics (M-BLAST), a dual-gated macrophage-mediated bacterial tumor-targeted delivery and in situ activation system. M-BLAST incorporates density-regulated virulence-enhanced attenuated Salmonella strains as the therapeutic core, thermally controlled gasdermin D N-terminal fragment (GSDMD-N)-expressing macrophages as the delivery vector, and copper selenide, a photothermal material, as a heat shock 'primer'. Following systemic administration, localized near-infrared (NIR) irradiation at the tumor site triggers macrophage pyroptosis, ensuring rapid and complete bacterial release. This disrupts the immunosuppressive tumor microenvironment (TME) and elicits a widespread cascading antitumor response, just like a 'immune bomb', while the dual-gating design of bacterial density and heat shock ensures safety by preventing off-target activation in non-tumor regions. Thus, M-BLAST could enhance the therapeutic utility of living engineered bacteria for cancer while ensuring safety for patients.