In situ programming of 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 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. Overall design: Single-cell sequencing analysis of mouse pancreatic cancer immune cells after treatment with administered drugs.