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, we 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. We 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.

许多对当前免疫疗法没有反应的癌症患者由于各种原因未能产生肿瘤特异性 T 细胞，例如缺乏将癌细胞识别为外来细胞的能力。在这里，我们提出了一种以前未知的方法，通过使用融合外泌体将融合病毒抗原 (VSV-G) 引入肿瘤细胞表面来对肿瘤进行异种化（将自身转变为非自身）。我们发现异种肿瘤细胞很容易被树突状细胞识别和吞噬。因此，肿瘤抗原被有效地呈递给T淋巴细胞。此外，外泌体-VSV-G 本身作为 TLR4 激动剂并刺激树突状细胞的成熟，导致 CD8 ⁺T细胞交叉引发。在多个肿瘤小鼠模型中施用这些外泌体使肿瘤细胞异种化，导致肿瘤生长抑制。抗 PD-L1 的联合治疗表现出完全的肿瘤消退 (30%) 和更好的长期总生存期。这些结果表明，融合外泌体的肿瘤异种化为癌症免疫治疗提供了一种以前未被识别的新策略。