In Situ Programming of the Tumor Microenvironment to Alleviate Immunosuppression for Pancreatic Cancer Immunotherapy.

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 tumor specificity, and potential to promote tumor immune evasion. To address these challenges, a novel exosome-based drug delivery platform, termed cmExo is developed, designed to precisely target and reprogram the tumor microenvironment (TME) in situ for pancreatic cancer immunotherapy. cmExo is engineered to encapsulate high copy numbers of IL-12 mRNA and 2'3'-cGAMP (cGAMP) and is functionalized with CD11b antibodies for targeted delivery to macrophages. Notably, cmExo facilitated the repolarization of M2 macrophages to M1 phenotype, thereby reprogramming the TME and enhancing the secretion of pro-inflammatory cytokines. This immunomodulatory effect reversed the immunosuppressive milieu of the TME and significantly inhibited tumor progression. More importantly, cmExo exhibited robust therapeutic efficacy in both murine pancreatic cancer and patient-derived xenograft models. These results suggest that cmExo represents a promising approach for overcoming immunosuppression in pancreatic cancer, paving the way for its potential application in cancer immunotherapy.