Zinc–Nickel\nBimetallic Hydroxide Nanosheets\nActivate the Paraptosis–Pyroptosis Positive Feedback Cycle\nfor Enhanced Tumor Immunotherapy

Immunotherapy holds significant promise for cancer treatment.\nHowever,\nthe highly immunosuppressive nature of solid tumors limits its effectiveness.\nHerein, we developed bioactive zinc–nickel hydroxide (ZnNi(OH)<sub>4</sub>) nanosheets (NSs) that can effectively initiate the paraptosis–pyroptosis\npositive feedback cycle through synergistic ionic effect, thereby\nmitigating the immunosuppression of solid tumors and enhancing the\nefficacy of immunotherapy. The acid-sensitive ZnNi(OH)<sub>4</sub> NSs releases Ni<sup>2+</sup> and Zn<sup>2+</sup> in the weakly acidic\ntumor microenvironment. The released Ni<sup>2+</sup> alleviated pyroptosis\ninhibition by inducing paraptosis and inhibiting autophagic flux.\nConcurrently, Ni<sup>2+</sup> triggered release of endogenous Zn<sup>2+</sup> within the cell through a coordination competition mechanism,\nfurther amplifying zinc overload-mediated pyroptosis. Interestingly,\npyroptosis-associated oxidative stress and endoplasmic reticulum stress\nfurther promote Ni<sup>2+</sup>-mediated paraptosis, forming a positive\nfeedback loop between pyroptosis and paraptosis. This process not\nonly effectively kills tumor cells but also stimulates a strong inflammatory\nresponse, enhancing the antitumor immune response and immunotherapy\nefficacy. Overall, this study proposes an effective paraptosis–pyroptosis\ninduction strategy based on metal ions and demonstrates the effectiveness\nof the positive feedback loop of paraptosis–pyroptosis in potentiating\nimmunotherapy.