Regulation of Ion Homeostasis for Enhanced Tumor Radio‐Immunotherapy

Abstract 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 (CaCO 3 ) nanoparticles and then modify theses nanoparticles with liposomes to obtain biocompatible CaCO 3 /CAI@Lipsome (CCL) for enhance tumor radio‐immunotherapy. CCL can specially decompose in tumor microenvironment, releasing calcium ion (Ca 2+ ) 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 Ca 2+ 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 Ca 2+ 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.