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.