Abstract

Current immunotherapies primarily focus on intratumoral immune suppression, with limited consideration of peripheral immune exhaustion, resulting in suboptimal clinical outcomes. Tumor-derived exosomes (TEXs) play a crucial role in both intratumoral immune suppression and peripheral immune exhaustion, making them an attractive target for cancer immunotherapy. In this study, we developed an optimized TEXs modulation strategy to enhance cancer immunotherapy by reprogramming the immune-promoting phenotype of TEXs and boosting their secretion. We designed a TEXs-tuning nanoassembly (TEXT) coloaded with biguanides and photosensitizers. The nanoassembly leverages hyaluronic acid for targeted accumulation at tumor sites. Biguanides inhibit the AMPK/Yap pathway in tumor cells, thereby reprogramming the tumor metabolic landscape and remodeling TEXs to an immune-promoting phenotype. Photodynamic therapy (PDT) is employed to boost the release of immune-promoting TEXs. Through the reprogramming of TEXs' phenotype and enhancement of their release, TEXT effectively alleviates immune exhaustion in peripheral tissues and reverses intratumoral immune suppression. TEXT effectively overcame both local and peripheral immunosuppression and demonstrated robust inhibition of primary and metastatic tumors as a monotherapy. Our findings highlight TEXT as an effective TEXs modulator, showcasing exosome regulation as a highly efficient and low-toxicity approach to combat cancer immune evasion. Overall, this strategy achieves a functional shift of TEXs from immunosuppressive factors to therapeutic synergists, establishing a paradigm of proactive immune modulation in cancer immunotherapy.