Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China.
Macao Institute of Materials Science and Engineering, Macau University of Science and Technology, Taipa, Macau SAR 999078, China.
ACS Nano. 2024 Oct 29;18(43):29913-29929. doi: 10.1021/acsnano.4c10378. Epub 2024 Oct 15.
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)) 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) NSs releases Ni and Zn in the weakly acidic tumor microenvironment. The released Ni alleviated pyroptosis inhibition by inducing paraptosis and inhibiting autophagic flux. Concurrently, Ni triggered release of endogenous Zn 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 Ni-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.
免疫疗法在癌症治疗方面具有重要的应用前景。然而，实体瘤高度免疫抑制的特性限制了其疗效。在此，我们开发了具有生物活性的锌镍氢氧化物（ZnNi(OH)）纳米片（NSs），通过协同离子效应有效引发细胞凋亡-细胞焦亡正反馈循环，从而减轻实体瘤的免疫抑制并增强免疫治疗的效果。在弱酸性肿瘤微环境中，酸敏感的 ZnNi(OH) NSs 会释放 Ni 和 Zn。释放的 Ni 通过诱导细胞凋亡和抑制自噬流来缓解细胞焦亡抑制。同时，Ni 通过配位竞争机制触发细胞内内源 Zn 的释放，进一步放大锌过载介导的细胞焦亡。有趣的是，细胞焦亡相关的氧化应激和内质网应激进一步促进了 Ni 诱导的细胞凋亡，在细胞焦亡和细胞凋亡之间形成正反馈循环。这一过程不仅能有效杀伤肿瘤细胞，还能刺激强烈的炎症反应，增强抗肿瘤免疫反应和免疫治疗效果。总的来说，本研究提出了一种基于金属离子的有效的细胞凋亡-细胞焦亡诱导策略，并证明了细胞凋亡-细胞焦亡正反馈循环在增强免疫治疗中的有效性。
