4.8 Article

Immunostimulant Hydrogel-Guided Tumor Microenvironment Reprogramming to Efficiently Potentiate Macrophage-Mediated Cellular Phagocytosis for Systemic Cancer Immunotherapy

Journal

ACS NANO
Volume 17, Issue 17, Pages 17217-17232

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acsnano.3c05093

Keywords

thermosensitive hydrogel; macrophage phagocytosis; CD47-SIRP & alpha; interaction; tumor microenvironment; antitumor immunotherapy

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Researchers successfully designed a hydrogel called TCCaGM, which enhanced macrophage-mediated phagocytosis through the encapsulation of GM-CSF and TCCaN. The hydrogel also improved the tumor microenvironment and accelerated the polarization of tumor-associated macrophages, leading to enhanced antitumor immune responses.
Macrophage-mediated cellular phagocytosis (MMCP) plays a critical role in conducting antitumor immunotherapy but is usually impaired by the intrinsic phagocytosis evading ability of tumor cells and the immunosuppressive tumor microenvironment (TME). Herein, a MMCP-boosting hydrogel (TCCaGM) was elaborately engineered by encapsulating granulocyte-macrophage colony-stimulating factor (GM-CSF) and a therapeutic nanoplatform (TCCaN) that preloaded with the tunicamycin (Tuni) and catalase (CAT) with the assistance of CaCO3 nanoparticles (NPs). Strikingly, the hypoxic/acidic TME was efficiently alleviated by the engineered hydrogel, eat me signal calreticulin (CRT) was upregulated, while the don't eat me signal CD47 was downregulated on tumor cells, and the infiltrated DCs were recruited and activated, all of which contributed to boosting the macrophage-mediated phagocytosis and initiating tumor-specific CD8(+) T cells responses. Meanwhile, the remodeled TME was beneficial to accelerate the polarization of tumor-associated macrophages (TAMs) to the antitumoral M1-like phenotype, further heightening tumoricidal immunity. With the combination of PD-1 antibody (aPD-1), the designed hydrogel significantly heightened systemic antitumor immune responses and long-term immunological effects to control the development of primary and distant tumors as well as suppress tumor metastasis and recurrence, which established an optimal strategy for high-performance antitumor immunotherapy.

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