Xenogenization by fusogenic exosomes in tumor microenvironment ignites and propagates antitumor immunity

Many cancer patients not responding to current immunotherapies fail to produce tumor-specific T cells for various reasons, such as a lack of recognition of cancer cells as foreign. Here, Korea University researchers suggest a previously unidentified method for xenogenizing (turning self to non-self) tumors by using fusogenic exosomes to introduce fusogenic viral antigens (VSV-G) onto the tumor cell surface. The researchers found that xenogenized tumor cells were readily recognized and engulfed by dendritic cells; thereby, tumor antigens were efficiently presented to T lymphocytes. Moreover, exosome–VSV-G itself acts as a TLR4 agonist and stimulates the maturation of dendritic cells, leading to CD8⁺ T cell cross-priming. The administration of these exosomes in multiple tumor mouse models xenogenized tumor cells, resulting in tumor growth inhibition. The combinatorial treatment with anti–PD-L1 exhibited complete tumor regression (30%) and better long-term overall survival. These results suggest that tumor xenogenization by fusogenic exosomes provides a previously unidentified novel strategy for cancer immunotherapy.

Schematic illustration of mVSVG-Exo–mediated tumor xenogenization strategy

(A) mVSVG-Exo fuses with the tumor cell membrane in an LDLR- and pH-dependent manner. (B) mVSVG-edited tumor cells are more easily engulfed by phagocytes. (C) mVSVG-Exo can activate DC functions by stimulating TLR4 signaling. This strategy enhances cross-prime ability, which can further increase CD8⁺ T cell immunity against cancer.