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

•CaCO3@PLGA can work as proton nanosponges to effective neutralize tumor acidity.•CaCO3@PLGA can promote the reinvigoration of both exhausted CD8 + T cells and activation of innate antitumor immunity.•CaCO3@PLGA can reinforce the therapeutic efficacy of various types of ICB immunotherapies.•Intratracheal administration of CaCO3@PLGA can synergize anti-PD-1 injection to effectively suppress lung metastasis. 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 nanosponge 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 activating 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 nanomedicine to generally reinforce ICB therapies toward diverse types of tumors by reversing tumor immunosuppression, promising for future clinical translation.