Unlocking a tumor-specific and self-amplifying "Zn2+ storm" via endogenous-exogenous synergy for potent pyroptosis-mediated antitumor immunotherapy.

Zinc ions (Zn2+) overload is considered an exceptionally safe and ideal approach for pyroptosis-mediated tumor treatment. However, achieving efficient and safe induction of tumor-specific Zn2+ overload remains a significant challenge. This study pioneers the concept of "sono-activated Zn2+ storm", developing a sono-activated and tumor microenvironment (TME)-responsive nanoplatform, Zn-TCPP@CaCO3, which enables a precise and spatiotemporally controllable induction of Zn2+ overload at the tumor site. Specifically, Zn-TCPP@CaCO3 selectively releases meso-tetra-(4-carboxyphenyl) porphine (TCPP) and delivers the "exogenous Zn2+" within the acidic TME. Upon tumor-site localized ultrasound irradiation, the sonosensitizer TCPP generates abundant reactive oxygen species (ROS) in situ, which oxidatively attack Zn-metallothionein complexes and effectively unlock the "endogenous Zn2+" reservoir. The synergistic influx of exogenous and endogenous Zn2+ drastically disrupts intracellular zinc homeostasis, further exacerbating oxidative stress by impairing mitochondrial function. This disruption initiates a self-amplifying positive feedback loop, ultimately inducing a potent "Zn2+ storm" that finally triggers tumor cell pyroptosis. The results demonstrate that this strategy not only effectively induces powerful antitumor effects, but also elicits a strong immunogenic response and significantly enhances the therapeutic efficacy of immune checkpoint inhibitors. Overall, this work provides valuable insights into the development of novel tumor specific ion interference therapies.