The modulation of tumor-associated macrophages via natural nanomodulators by neutralizing the acidic tumor microenvironment for tumor treatment

Tumor-associated macrophages (TAMs) account for nearly half the mass of solid tumors. A number of studies show that TAMs are similar to M2 macrophages, which have strong immunosuppressive activity. Manipulation of the phenotype of TAMs is a novel and potential therapeutic approach to enhance antitumor immunity. Based on this, this paper comprehensively reveals that immunomodulator β-glucan (Glu) could not fully exert its role in reversing macrophage polarization under acidic conditions, and calcium carbonate improved the role of Glu by neutralizing the acidic environment. To be specific, by constructing a Glu and calcium carbonate co-precipitation system (Glu-VCC), Glu-VCC could exhibit a stronger immune-activating effect through a cascade reaction with its ability to continuously regulate the tumor microenvironment. Glu-VCC nanoparticles can raise the pH of the tumor tissue from 6.7 to 7.0 and increase M1-like macrophages by 57% compared to the limited reversal ability of Glu toward TAMs. In addition, Glu-VCC showed excellent tumor clearance in in vivo experiments. These results not only expand the use of calcium carbonate in the delivery of drugs but also provide new ideas for tumor immunotherapy.