Triple‐Kill Nano‐Disruptor Integrating Ion Interference, Metabolic Inhibition, and Immune Activation for Augmented Apoptosis and Pyroptosis‐Mediated Immunotherapy

Abstract

Abstract Ion‐overload‐mediated pyroptosis can enhance cytotoxic T‐cell infiltration and systemic immunity, presenting a promising strategy to strengthen immunotherapy efficacy. However, the low frequency of pro‐inflammatory immune cells and the immunosuppressive tumor network pose substantial challenges to achieving potent immunogenic cell death. This study designs a multiphase phase‐transition nano‐disruptor (V‐MoS 2 &CaF 2 @HA), inspired by ionic interference and metabolic inhibition, to target multiple immunosuppressive mechanisms in tumors. Vanadium‐doping engineering induces the coexistence of the 2H (semiconducting) and 1T (metallic) phases, maximizing the ability of piezocatalysts to enhance charge‐carrier mobility. Critically, V‐MoS 2 with its ultrathin, asymmetrical layered architecture, reinforces the piezoelectric response by promoting band bending and charge‐carrier separation, thereby establishing favorable conditions for efficient electron–hole separation and reactive oxygen species generation. Concurrently, calcium‐ion self‐amplifying leakage and hydrogen sulfide liberation collectively create an “ion‐interference–metabolic‐hijacking” effect that induces oxidative stress, amplifies innate immune cGAS–STING pathway activation, and triggers a pyroptosis–apoptosis cross‐death effect and immune activation. Thus, the study offers a straightforward strategy to achieve antitumor immunity through STING pathway activation and provides a new avenue to robustly activate immunogenic cell death for tumor treatment.