A polymeric nanoplatform enhances the cGAS-STING pathway in macrophages to potentiate phagocytosis for cancer immunotherapy

Jul 22, 2024Journal of controlled release : official journal of the Controlled Release Society

A polymer-based system boosts immune cell cancer-fighting by activating the cGAS-STING pathway to improve cancer immunotherapy

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Abstract

The mannose-modified nanoplatform M-PNP@R@C significantly inhibits tumor growth in melanoma graft tumor models.

Immunosuppressive tumor-associated macrophages (TAMs) are prevalent in tumor tissue and hinder effective immune responses.
SIRPα expression in TAMs negatively impacts macrophage activation and phagocytosis, allowing tumors to evade immune detection.
Co-delivery of R848 and cGAMP promotes the transformation of TAMs from an anti-inflammatory state to a pro-inflammatory state.
Activation of the STING pathway in TAMs leads to reduced SIRPα expression through modulation of fatty acid oxidation metabolism.
Combination treatment with anti-CD47 and programmed death ligand-1 antibodies improves survival rates and reduces lung metastasis.

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Immunosuppressive tumor-associated macrophages (TAMs) account for a high proportion of the tumor tissue and significantly impede immunoefficacy. Furthermore, the signal regulatory protein α (SIRPα) expressed in TAMs adversely correlates with macrophage activation and phagocytosis, resulting in immunosurveillance escape. To address these difficulties, a mannose-modified, pH-responsive nanoplatform with resiquimod (R848) and 2', 3'-cyclic GMP-AMP (cGAMP) co-encapsulation (named M-PNP@R@C) is designed to polarize TAMs and lower SIRPα expression. The co-delivery of R848 and cGAMP synergistically facilitates the polarization of TAMs from the anti-inflammatory M2 phenotype into the pro-inflammatory M1 phenotype, thereby enhancing antitumor immunotherapy. Remarkably, activation of the cGAMP-mediated stimulator of interferon genes (STING) in TAMs significantly downregulates the expression of SIRPα, which synergizes with the cluster of differentiation 47 (CD47) antibody for the dual blockade of the CD47-SIRPα axis. Further analysis of single-cell RNA sequencing indicates that STING activation downregulates SIRPα by regulating intracellular fatty acid oxidation metabolism. In vivo studies indicate that M-PNP@R@C significantly inhibits tumor growth with a potent antitumor immune response in melanoma graft tumor models. After synergy with anti-CD47, the double blockade strategies of the SIRPα/CD47 axis result in a notable inhibition of lung metastasis. A prolonged survival rate is observed after combination treatment with CD47 and programmed death ligand-1 antibodies for the triple immune checkpoint blockade. In summary, our study provides original insights into the potential role of the STING pathway in macrophage-based immunotherapy, thus offering a potential combinatorial strategy for cancer therapy.

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A polymeric nanoplatform enhances the cGAS-STING pathway in macrophages to potentiate phagocytosis for cancer immunotherapy

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