Precision nanotherapy remodels the tumor-associated macrophage to reverse immunnosuppressive in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive stroma rich in tumor-associated macrophages (TAMs) that limit the therapeutic efficacy. We introduce a TAM-targeted nanotherapy platform that selectively delivers either a CSF1R inhibitor or the STING agonist cGAMP to immunosuppressive TAMs. While CSF1R inhibitor–loaded nanoparticles efficiently depleted TAMs and produced moderate antitumor effects, TAM-targeted cGAMP nanoparticles reprogrammed TAMs into immune-stimulating effectors. This reprogramming normalized aberrant vasculature, alleviated desmoplasia, and enhanced infiltration and activation of cytotoxic immune cells. In combination with gemcitabine, PD-1 checkpoint blockade, or CAR-NK cell therapy, TAM-targeted STING activation provided an in situ immunostimulatory signal that markedly improved antitumor efficacy in preclinical PDAC models. Ex vivo efficacy in human PDAC tissues and a favorable safety profile show the translational potential of this TAM-targeted nanotherapy to overcome the immune desert of PDAC. Overall design: Comparative gene expression profiling analysis of RNA-seq data for murine PDAC tumors with or without treatment of TAM-cGAMPnp