A NEW study has unveiled a groundbreaking cancer treatment approach using engineered extracellular vesicles to target both tumor cells and immunosuppressive stromal cells in the tumor microenvironment (TME). This innovative therapy holds promise for improving outcomes in patients with difficult-to-treat cancers.
The study highlighted the engineering of small extracellular vesicles (sEVs) derived from natural killer (NK) cells. These nanosized vesicles are equipped with a death receptor 5 (DR5) agonistic single-chain variable fragment (scFv), which triggers extrinsic apoptosis. By employing the PDGFR transmembrane domain, researchers successfully delivered DR5-scFvs to the surface of the vesicles, enhancing their precision in targeting DR5-positive (DR5+) cells.
When tested, DR5-scFv sEVs exhibited a powerful dual-action mechanism. The vesicles induced rapid apoptosis in DR5+ cancer cells, as well as in immunosuppressive stromal cells, including myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs). This dual targeting capability is particularly significant, as the TME often shields tumors from the immune system and hinders the efficacy of conventional therapies.
In preclinical studies, systemic delivery of DR5-scFv sEVs showed remarkable efficacy in inhibiting the growth of DR5+ melanoma, liver cancer, and breast cancer. Treated mice experienced significantly prolonged survival without notable toxicity, underscoring the safety profile of this approach. Notably, the vesicles demonstrated superior performance compared to traditional DR5 antibodies.
Additionally, in organotypic patient-derived melanoma slice cultures, the vesicles effectively reduced melanoma cell proliferation, suppressed MDSCs, and activated CD8+ T cells. These findings suggest the potential for not only direct tumor cell elimination but also enhanced immune system engagement.
This study demonstrated the potential of engineered sEVs to overcome the challenges posed by the TME. While further research and clinical trials are needed, this approach offers hope for improved therapeutic strategies in treating advanced cancers with fewer side effects.
Reference: Guo Y et al. Engineered extracellular vesicles with DR5 agonistic scFvs simultaneously target tumor and immunosuppressive stromal cells. Sci Adv. 2025;11(3).
Anaya Malik | AMJ
