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^aCD11b is developed, designed to precisely target and reprogram the tumor microenvironment (TME) in situ for pancreatic cancer immunotherapy. cmExo^aCD11b 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^aCD11b 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^aCD11b exhibited robust therapeutic efficacy in both murine pancreatic cancer and patient-derived xenograft models. These results suggest that cmExo^aCD11b represents a promising approach for overcoming immunosuppression in pancreatic cancer, paving the way for its potential application in cancer immunotherapy.