Ions play a vital role in regulating various biologicalprocesses,including metabolic and immune homeostasis, which involves tumorigenesisand therapy. Thus, the perturbation of ion homeostasis can inducetumor cell death and evoke immune responses, providing specific antitumoreffects. However, antitumor strategies that exploit the effects ofmultiion perturbation are rare. We herein prepared a pH-responsivenanomodulator by coloading curcumin (CU, a Ca2+ enhancer)with CaCO3 and MnO2 into nanoparticles coatedwith a cancer cell membrane. This nanoplatform was aimed at reprogrammingthe tumor microenvironment (TME) and providing an antitumor treatmentthrough ion fluctuation. The obtained nanoplatform, called CM NPs,could neutralize protons by decomposing CaCO3 and attenuatingcellular acidity, they could generate Ca2+ and releaseCU, elevating Ca2+ levels and promoting ROS generationin the mitochondria and endoplasmic reticulum, thus, inducing immunogeniccell death. Mn2+ could decompose the endogenous H2O2 into O-2 to relieve hypoxia and enhance thesensitivity of cGAS, activating the cGAS-STING signaling pathway.In addition, this strategy allowed the reprogramming of the immuneTME, inducing macrophage polarization and dendritic cell maturationvia antigen cross-presentation, thereby increasing the immune system'sability to combat the tumor effectively. Moreover, the as-preparednanoparticles enhanced the antitumor responses of the & alpha;PD1 treatment.This study proposes an effective strategy to combat tumors via thereprogramming of the tumor TME and the alteration of essential ionsconcentrations. Thus, it shows great potential for future clinicalapplications as a complementary approach along with other multimodaltreatment strategies.