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

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-MoS₂&CaF₂@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-MoS₂ 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.