离子在调节多个生物过程中起着重要作用，包括代谢和免疫稳态，涉及肿瘤发生和治疗。因此，离子稳态的扰动可以引起肿瘤细胞死亡并唤起免疫反应，提供特异性的抗肿瘤效应。然而，利用多离子扰动效应的抗肿瘤策略很少。我们在此制备了一种pH响应的纳米调节器，将姜黄素（一种Ca2+增强剂）与碳酸钙和二氧化锰共载入涂有癌细胞膜的纳米颗粒中。该纳米平台旨在通过离子波动来重新调节肿瘤微环境（TME）并提供抗肿瘤治疗。所得到的纳米平台被称为CM NPs，它们可以通过分解碳酸钙和减弱细胞酸度中和质子，可以产生Ca2+并释放姜黄素，从而提高Ca2+水平并促进线粒体和内质网中的ROS生成，从而诱导免疫原性细胞死亡。Mn2+可以将内源性H2O2分解为O2以缓解缺氧，并增强cGAS的敏感性，激活cGAS-STING信号通路。此外，这种策略通过抗原交呈诱导巨噬细胞极化和树突状细胞成熟，实现了免疫TME的重新编程，从而增强免疫系统对肿瘤的有效抗击能力。此外，制备的纳米颗粒增强了αPD1治疗的抗肿瘤反应。本研究提出了一种通过调节肿瘤TME和改变必需离子浓度来对抗肿瘤的有效策略，因此，它在未来的临床应用中作为一种辅助手段与其他多模式治疗策略相结合具有巨大潜力。

Ions play a vital role in regulating various biological processes, including metabolic and immune homeostasis, which involves tumorigenesis and therapy. Thus, the perturbation of ion homeostasis can induce tumor cell death and evoke immune responses, providing specific antitumor effects. However, antitumor strategies that exploit the effects of multiion perturbation are rare. We herein prepared a pH-responsive nanomodulator by coloading curcumin (CU, a Ca2+ enhancer) with CaCO3 and MnO2 into nanoparticles coated with a cancer cell membrane. This nanoplatform was aimed at reprogramming the tumor microenvironment (TME) and providing an antitumor treatment through ion fluctuation. The obtained nanoplatform, called CM NPs, could neutralize protons by decomposing CaCO3 and attenuating cellular acidity, they could generate Ca2+ and release CU, elevating Ca2+ levels and promoting ROS generation in the mitochondria and endoplasmic reticulum, thus, inducing immunogenic cell death. Mn2+ could decompose the endogenous H2O2 into O2 to relieve hypoxia and enhance the sensitivity of cGAS, activating the cGAS-STING signaling pathway. In addition, this strategy allowed the reprogramming of the immune TME, inducing macrophage polarization and dendritic cell maturation via antigen cross-presentation, thereby increasing the immune system's ability to combat the tumor effectively. Moreover, the as-prepared nanoparticles enhanced the antitumor responses of the αPD1 treatment. This study proposes an effective strategy to combat tumors via the reprogramming of the tumor TME and the alteration of essential ions concentrations. Thus, it shows great potential for future clinical applications as a complementary approach along with other multimodal treatment strategies.