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 cmExoaCD11b is developed, designed to precisely target and reprogram the tumor microenvironment (TME) in situ for pancreatic cancer immunotherapy. cmExoaCD11b 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, cmExoaCD11b 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, cmExoaCD11b exhibited robust therapeutic efficacy in both murine pancreatic cancer and patient-derived xenograft models. These results suggest that cmExoaCD11b represents a promising approach for overcoming immunosuppression in pancreatic cancer, paving the way for its potential application in cancer immunotherapy.