Immunotherapy holds significant promise for cancer treatment. However, the highly immunosuppressive nature of solid tumors limits its effectiveness. Herein, we developed bioactive zinc-nickel hydroxide (ZnNi(OH)4) nanosheets (NSs) that can effectively initiate the paraptosis-pyroptosis positive feedback cycle through synergistic ionic effect, thereby mitigating the immunosuppression of solid tumors and enhancing the efficacy of immunotherapy. The acid-sensitive ZnNi(OH)4 NSs releases Ni2+ and Zn2+ in the weakly acidic tumor microenvironment. The released Ni2+ alleviated pyroptosis inhibition by inducing paraptosis and inhibiting autophagic flux. Concurrently, Ni2+ triggered release of endogenous Zn2+ within the cell through a coordination competition mechanism, further amplifying zinc overload-mediated pyroptosis. Interestingly, pyroptosis-associated oxidative stress and endoplasmic reticulum stress further promote Ni2+-mediated paraptosis, forming a positive feedback loop between pyroptosis and paraptosis. This process not only effectively kills tumor cells but also stimulates a strong inflammatory response, enhancing the antitumor immune response and immunotherapy efficacy. Overall, this study proposes an effective paraptosis-pyroptosis induction strategy based on metal ions and demonstrates the effectiveness of the positive feedback loop of paraptosis-pyroptosis in potentiating immunotherapy.
Keywords: bimetallic hydroxide; immunotherapy; ion interference; paraptosis; pyroptosis.