Controlled pyroptosis of engineered macrophages enables biphasic antitumor via the release of oncolytic bacteria and inflammatory signals

Engineered macrophage-based therapies offer promising potential for cancer treatment but are limited by slow, uncontrolled drug release and the risk of macrophage reprogramming into tumor-promoting phenotypes. Here, we developed a thermally induced macrophage autolysis release system, the macrophage-microbe encapsulation bomb (MME-Bomb), which combines engineered macrophages loaded with indocyanine green-encapsulated nanoparticles and an antitumor attenuated Salmonella typhimurium strain. Photothermal therapy is used to induce controlled pyroptosis and rupture of the encapsulated macrophages within the tumor microenvironment, releasing intracellular bacteria to stimulate prolonged antitumor immunity. By integrating light-responsive biomodulation, our approach enables site-specific activation of engineered cells, enhancing the rapid delivery of therapeutic agents and maximizing the synergy between macrophage-based and bacterial therapies. In preclinical cancer models, the MME-Bomb significantly reduced the tumor burden and improved survival outcomes, both alone and in combination with checkpoint inhibitors. This innovative strategy offers a versatile and precise framework for advancing cancer immunotherapies.