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In situ programming of tumor microenvironment to alleviate immunosuppression for pancreatic cancer immunotherapy

ABSTRACT: Recent studies have highlighted the pivotal role of the cGAS-STING pathway in cancer immunotherapy. However, clinical trials with cGAS-STING pathway agonists have faced setbacks thanks to their short biological half-life, lack of specificity, and potential to promote tumor immune evasion. To address these challenges, we developed a novel drug delivery platform, termed cmExoaCD11b, designed to precisely target and reprogram the tumor microenvironment (TME) in situ for pancreatic cancer immunotherapy. cmExoaCD11b was engineered to encapsulate high copy numbers of cGAMP and IL-12 mRNA using cellular nanoporation technology and was functionalized with anti-CD11b antibodies for targeted delivery to macrophages. Notably, cmExoaCD11b facilitates the repolarization of M2 macrophages to M1 phenotype, thereby reprograming the TME and enhancing the release of pro-inflammatory cytokines. cmExoaCD11b successfully reversed the immunosuppressive status in the TME and suppressed tumor growth. More importantly, cmExoaCD11b has demonstrated significant therapeutic efficacy in both murine pancreatic cancer models and patient-derived xenograft models. These results suggest that cmExoaCD11b represents a promising approach to overcoming immunosuppression in pancreatic cancer, paving the way for its potential application in cancer immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE294507 | GEO | 2025/09/24

REPOSITORIES: GEO

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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.

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In situ programming of tumor microenvironment to alleviate immunosuppression for pancreatic cancer immunotherapy

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