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Purpose: Cancer immunotherapy aims to enhance the immune system’s ability to recognize and eliminate cancer cells, providing a sustained and effective immune response. However, the tumor microenvironment (TME), characterized by an abundance of tumor-associated M2 macrophages and the presence of exhausted or naïve T cells (non-effector T cells), remains a major barrier to effective immunotherapy. Herein, inflammatory M1 macrophage-derived extracellular vesicles (M1EV) were surface-modified to display interleukin-2 (M1EVIL2), aiming to develop a multifunctional cancer immunotherapeutic agent capable of modulating both innate and adaptive immune responses. Methods: We engineered M1EV to label the surface with azide groups through metabolic glycoengineering and developed M1EVIL2 that displayed IL-2 via bioorthogonal chemistry. M1EVIL2 were purified by size-exclusion chromatography (SEC) and characterized through comprehensive analyses, including nanoparticle tracking analysis (NTA). In vitro macrophage repolarization and T cell activation were evaluated at the gene-expression level, followed by ex vivo assays assessing T-cell proliferation, cytokine secretion, and activation marker expression. Results: M1EVIL2 effectively retained the intrinsic physicochemical properties of EVs while displaying IL-2 stably on its surface. It upregulated M1 macrophage markers, IL-1β and CXCL10, while downregulating the M2 macrophage marker CD206, thereby inducing M2-to-M1 macrophage repolarization. In addition, M1EVIL2 also activated CD4 + T cells and induced the activation of naïve CD8 + T cells to effector T cells, leading to enhanced cell proliferation and secretion of antitumor cytokines. Conclusion: These results indicate that M1EVIL2 has the potential to reshape the tumor immune landscape by simultaneously activating macrophages and T cells, thereby enhancing both innate and adaptive immune responses. Unlike conventional cancer therapies, which directly target tumor cells, M1EVIL2 is expected to enhance immune responses, potentially mitigating adverse effects while improving therapeutic efficacy. Keywords: cancer immunotherapy, extracellular vesicles, interleukin-2, macrophage repolarization, T cell activation
Kim et al. (Sat,) studied this question.