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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE310136 | GEO | 2025/12/01

REPOSITORIES: GEO

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Project description:High-grade gliomas, the most common and aggressive primary brain tumors, are characterized by a complex and multifaceted tumor microenvironment (TME). Among the non-malignant cells of the glioma TME, tumor-associated microglia and macrophages (TAMs) constitute the major compartment. In patients, a greater abundance of TAMs is associated with high-grade and more aggressive disease. In a range of glioma mouse models, we have observed specific alterations in TAM dynamics and functions during tumor development and following different therapeutic interventions, including irradiation. The underlying TAM abundance may also modulate the subsequent response to TAM-targeted therapy, including the anti-CSF1R inhibitor BLZ945, which results in a pronounced tumor regression in different preclinical models of brain cancers, as our lab has recently shown. These observations indicate that it is crucial to evaluate TAM abundance and dynamics in gliomas. Current techniques to quantify TAMs in patients rely mainly on histological staining of tumor biopsies. While informative, these techniques require an invasive procedure to harvest the tissue sample and typically only result in a snapshot of a small region at a single point in time. Fluorine isotope 19 MRI (19F MRI) has been shown to be a powerful tool to non-invasively and longitudinally monitor myeloid cells in other pathological conditions by injecting perfluorocarbon-containing nanoparticles (PFC-NP). In this study, we demonstrated the feasibility and power of 19F MRI in preclinical glioma models and brain metastasis models and showed that the major cellular source of 19F signal consists of TAMs. Moreover, PFC-NP accumulation occurred predominantly in proximity to dysmorphic vessels, thereby enabling the identification of a TAM subpopulation with a specific oxidative metabolism. We also evaluated this imaging modality in the context of irradiation (IR) treatment and found that the 19F signal enables the tracking of TAM dynamics over time following IR. Moreover, multispectral 19F MRI with two different PFC-NP allowed us to identify spatially- and temporally-distinct TAM niches in IR-recurrent tumors. Together, we have been able to image TAMs non-invasively and longitudinally with a powerful integrated cellular, spatial and temporal resolution, while revealing new biological insights into the many functions of TAMs, including in disease recurrence.

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

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