细胞内/外离子含量影响肿瘤细胞的生长和转移，以及各种抗肿瘤治疗的疗效。本文将一种碳酸酐酶抑制剂（CAI）加载到pH响应型碳酸钙（CaCO3）纳米颗粒上，然后用脂质体修饰这些纳米颗粒，以获得生物相容性的CaCO3/CAI@脂质体（CCL），以增强肿瘤放射免疫治疗的效果。CCL能够在肿瘤微环境中特异性分解，释放出钙离子（Ca2+）和CAI，同时增加细胞外液的pH值。CAI抑制了肿瘤细胞内外氢离子（H+）的流动，从而使肿瘤酸性微环境逆转并增加细胞内H+的浓度，这两者都能提高肿瘤对放疗的敏感性。随后，增加的细胞内H+和放疗引起的反应性氧化物促进钙离子的流入，导致细胞钙超载。此外，CCL调控的H+和Ca2+含量增强了放疗诱导的免疫细胞死亡和树突状细胞成熟，增强全身抗肿瘤适应性免疫。同时，在X射线暴露下，CCL处理后的肿瘤中的巨噬细胞由促肿瘤的M2型向抗肿瘤的M1型极化，这是由于肿瘤酸性微环境的中和和钙含量的增加。因此，通过简单的纳米制备多方面调节肿瘤细胞内/外的pH/钙离子，可以提高放射免疫治疗的疗效。© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.

Intra/extracellular ion content affects the growth and metastasis of tumor cells, as well as the efficacy of various antitumor therapies. Herein, a carbonic anhydrase inhibitor (CAI) is loaded onto pH-responsive calcium carbonate (CaCO3 ) nanoparticles and then modify theses nanoparticles with liposomes to obtain biocompatible CaCO3 /CAI@Lipsome (CCL) for enhance tumor radio-immunotherapy. CCL can specially decompose in tumor microenvironment, releasing calcium ion (Ca2+ ) and CAI, as well as increasing the pH value of extracellular fluid. CAI restrains the flow of hydrogen ion (H+ ) inside and outside the tumor cells, resulting in the reversal of tumor acidic microenvironment and the increase of intracellular H+ , both of which can improve the sensitivity of tumor to radiotherapy. Afterward, the increased intracellular H+ together with radiotherapy-causes reactive oxygen species promotes calcium influx, leading to cellular calcium overload. Moreover, the CCL-tailored content of H+ and Ca2+ strengthens radiotherapy-induced immunogenic cell death and dendritic cell maturation, amplifying systemic anti-tumor adaptive immunity. Meanwhile, macrophages in the CCL-treated tumors are polarized from pro-tumor M2 to anti-tumor M1 under X-ray exposure, owing to the neutralization of tumor acidic microenvironment and enhances Ca2+ content. Therefore, multi-directional regulation of the intra/extra tumor cell pH/calcium by simple nano-preparation would provide a powerful way to improve the efficacy of radio-immunotherapy.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.