CaCO3 based proton nanosponge to potentiate immune checkpoint blockade therapy by synergistically reversing tumor immunosuppression

Tumor acidity presents one of the leading causes of tumor immunosuppression (e.g., exhaustion of effector T cells), thereby remarkably attenuating the potency of current immune checkpoint blockade (ICB) therapy in controlling tumor progression. Here, we report that calcium carbonate encapsulated with copolymers of poly (lactic-co-glycolic acid) (PLGA) and PLGA-poly(ethylene glycol) (PLGA-PEG) can work as a proton nano -sponge to neutralize tumor acidity by reacting with protons post intravenous administration. The obtained CaCO3@PLGA NPs can thus promote the reinvigoration of both exhausted CD8+ T cells and innate antitumor immunity. As a result, CaCO3@PLGA NP administration could potentiate the therapeutic efficacies of three ICB therapies toward both CT26 and B16F10 tumor xenografts by preventing exhaustion of CD8+ T cells and acti-vating innate antitumor immunity. Furthermore, we further demonstrate that intratracheal administration of CaCO3@PLGA NPs effectively suppressed lung metastasis of B16F10 melanoma when synergized with systemic anti-PD-1 administration. This work highlights that CaCO3 nanoparticles could be an effective yet safe nano -medicine to generally reinforce ICB therapies toward diverse types of tumors by reversing tumor immunosup-pression, promising for future clinical translation.