Coordination Polymer‐Coated CaCO₃ Reinforces Radiotherapy by Reprogramming the Immunosuppressive Metabolic Microenvironment

Abstract Radiotherapy is widely exploited for the treatment of a large range of cancers in clinic, but its therapeutic effectiveness is seriously crippled by the tumor immunosuppression, mainly driven by the altered metabolism of cancer cells. Here, a pH‐responsive nanomedicine is prepared by coating calcium carbonate (CaCO₃) nanoparticles with 4‐phenylimidazole (4PI), an inhibitor against indoleamine 2,3‐dioxygenase 1 (IDO‐1), together with zinc ions via the coordination reaction, aiming at reinforcing the treatment outcome of radiotherapy. The obtained pH‐responsive nanomedicine, coined as acidity‐IDO1‐modulation nanoparticles (AIM NPs), is able to instantly neutralize protons, and release 4PI to suppress the IDO1‐mediated production of kynurenine (Kyn) upon tumor accumulation. As a result, treatment with AIM NPs can remarkably enhance the therapeutic efficacy of radiotherapy against both murine CT26 and 4T1 tumors by eliciting potent antitumor immunity. Furthermore, it is shown that such combination treatment can effectively suppress the growth of untreated distant tumors via the abscopal effect, and result in immune memory responses to reject rechallenged tumors. This work highlights a novel strategy of simultaneous tumor acidity neutralization and IDO1 inhibition to potentiate radiotherapy, with great promises to suppress tumor metastasis and recurrence by eliciting robust antitumor immunity.