Near-Infrared-Triggered Photoresponsive Nanobombs Overcome Tumor Immunosuppression through Coordinated Pyroptosis Activation and Mitophagy Blockade.

Abstract

Solid tumors resemble fortified hypoxic bastions with multifaceted defense mechanisms, wherein the synergistic interplay of hypoxia and immunosuppressive networks severely limits conventional therapies. While reactive oxygen species (ROS)-induced pyroptosis holds promise for remodeling the immunosuppressive tumor microenvironment (TME) and potentiating antitumor immunity, mitochondrial autophagy-mediated oxidative damage repair in cancer cells critically attenuates its efficacy. To address this, we engineered a near-infrared (NIR)-activated ″photocontrolled nanobomb″ (PPLs) that integrates tumor-targeted ROS generation, self-accelerating disintegration, pyroptosis induction, and mitochondrial autophagy blockade for precision ″fortress″ dismantling. Upon NIR irradiation, PPLs rapidly produce cytotoxic ROS, triggering Caspase-1-dependent pyroptosis while undergoing programmed structural collapse. Concurrently, the released lonidamine (LND) inhibits HK2-driven mitochondrial autophagy, synergistically amplifying oxidative damage and immunogenic cell death. This dual-action strategy effectively reprograms the immunosuppressive TME by enhancing dendritic cell maturation and cytotoxic T lymphocyte infiltration, establishing a pro-inflammatory antitumor niche. Our work not only presents an NIR-responsive nanoplatform for spatiotemporal tumor eradication but also deciphers the mechanistic synergy between pyroptosis and mitochondrial autophagy inhibition, offering an effective path for combinatorial immunotherapy.