PlP-powered exosomal therapeutics: Redefining immune activation in therapy-resistant tumor microenvironment.

Abstract

e14512 Background: Tumor immunosuppression is a major obstacle in developing effective oncological therapies, particularly in pediatric, adolescent, young, and elderly adults with advanced or therapy-resistant cancers. These tumors create a microenvironment that suppresses immune responses, enabling unchecked growth. Functionalized exosomes derived from dendritic cells pre-conditioned (EDCD-PC) with the Phospholipoproteomic Complex (PLP) offer a groundbreaking approach to reprogramming the tumor microenvironment (TME). These exosomes modulate key immune pathways, promoting a pro-inflammatory Th1/Th2 balance and reducing immunosuppressive cytokines. This dual-action restores the immune system's ability to target and eliminate tumors while adapting to diverse therapeutic needs, offering personalized options. Methods: Semi-immortalized dendritic cells were pre-conditioned with PLP (50 µg/mL) for 24 hours before generating functionalized exosomes. These exosomes were evaluated in ZR-75-30 (breast) and HT-29 (colon) tumor cell lines through treatments with 10, 50, and 100 µg/mL for 72 hours. Key cytokines (IL-12, IFN-γ, IL-10) were quantified by Cytometric Bead Array (CBA), and apoptosis was assessed by Annexin V/PI staining and caspase-3 activation. Results: Immunological Modulation: o Increase in IL-12 (+57.6%, p < 0.001) and IFN-γ (+55.4%, p < 0.001). o Reduction in IL-10 (-42.3%, p < 0.01), favoring a pro-inflammatory Th1/Th2 balance. Tumor Apoptosis: o 46.3% ± 1.7 apoptosis in ZR-75-30 and 43.5% ± 2.1 in HT-29 (p < 0.01). Targeted Efficacy: o High specificity in immunosuppressive tumors, underscoring its relevance in resistant tumors. Conclusions: Functionalized exosomes derived from dendritic cells pre-conditioned with PLP represent a significant advancement in precision oncology, particularly for addressing immunosuppressive and therapy-resistant tumors. These exosomes demonstrate a unique ability to modulate the tumor microenvironment by promoting pro-inflammatory responses while reducing immunosuppressive signaling, thereby restoring immune surveillance. This dual-action mechanism not only facilitates tumor regression but also enhances the efficacy of existing treatments when used in combination. The clinical relevance of EDCD-PC exosomes extends across a broad spectrum of patients, including pediatric, adolescent, young adult, and elderly populations. Their personalization and scalability ensure adaptability to various clinical scenarios, making them an invaluable tool for TME reprogramming, ensures the stability and global applicability of these exosomes, overcoming logistical barriers in resource-limited regions.