Tumor Microenvironment Modulating CaCO_3-Based Colloidosomal Microreactors Can Generally Reinforce Cancer Immunotherapy

摘要

Tumor hypoxia and acidity, two general features of solid tumors, are known tohave negative effect on cancer immunotherapy by directly causingdysfunction of effector immune cells and promoting suppressive immunecells inside tumors. Herein, a multifunctional colloidosomal microreactor isconstructed by encapsulating catalase within calcium carbonate (CaCO_3)nanoparticle-assembled colloidosomes (abbreviated as CaP CSs) via theclassic double emulsion method. The yielded CCaP CSs exhibit well-retainedproton-scavenging and hydrogen peroxide decomposition performances andcan thus neutralize tumor acidity, attenuate tumor hypoxia, and suppresslactate production upon intratumoral administration. Consequently, CCaP CSstreatment can activate potent antitumor immunity and thus significantlyenhance the therapeutic potency of coloaded anti-programmed death-1(anti-PD-1) antibodies in both murine subcutaneous CT26 and orthotopic 4T1tumor xenografts. In addition, such CCaP CSs treatment also markedlyreinforces the therapeutic potency of epidermal growth factor receptorexpressing chimeric antigen receptor T (EGFR-CAR-T) cells toward a humantriple-negative breast cancer xenograft by promoting their tumor infiltrationand effector cytokine secretion. Therefore, this study highlights that chemicalmodulation of tumor acidity and hypoxia can collectively reverse tumorimmunosuppression and thus significantly potentiate both immunecheckpoint blockade and CAR-T cell immunotherapies toward solid tumors.