Multifunctional Calcium–Manganese Nanomodulator Provides Antitumor Treatment and Improved Immunotherapy via Reprogramming of the Tumor Microenvironment

[Image: see text] 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 Ca(2+) enhancer) with CaCO(3) and MnO(2) 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 CaCO(3) and attenuating cellular acidity, they could generate Ca(2+) and release CU, elevating Ca(2+) levels and promoting ROS generation in the mitochondria and endoplasmic reticulum, thus, inducing immunogenic cell death. Mn(2+) could decompose the endogenous H(2)O(2) into O(2) 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.