Gao Yifan, Liu Jinzhao, Wu Meicen, Zhang Yanmei, Wang Manni, Lyu Qingyang, Zhang Wenyue, Zhou Yang, Cheuk Yin Celeste, Wang Xiwei, Liu Yinping, Wang Weiping, Tu Wenwei
Department of Paediatrics & Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR, China.
ACS Nano. 2025 Feb 4;19(4):4251-4268. doi: 10.1021/acsnano.4c11024. Epub 2025 Jan 25.
Melanoma is the most aggressive type of skin cancers. Traditional chemotherapy and radiotherapy have limited effectiveness and can lead to systemic side effects. Photodynamic therapy (PDT) is a photoresponsive cancer therapy based on photosensitizers to generate reactive oxygen species (ROS) to eradicate tumor cells. Our previous study showed that exosomes derived from human γδ-T cells (γδ-T exosomes) could control Epstein-Barr virus-associated tumors. Here, we combined γδ-T exosomes and PDT for targeted photoimmunotherapy by membrane fusion of γδ-T exosomes and Chlorin e6 (Ce6)-loaded liposomes. The functional surface proteins, such as CCR5 and PD-1, on the hybrid exosomes mediated the specific binding of hybrid exosomes toward melanoma tissues. The cytolytic molecules, such as granzyme A, granzyme B, perforin, and granulysin from γδ-T exosomes, induced specific apoptosis of cancer cells without harming normal cells. In response to light irradiation, ROS generation inside melanoma cells synergized with cytolytic molecules to induce apoptosis and promote immunogenic cancer cell death (ICD). The subsequently released damage-associated molecular patterns (DAMPs) could stimulate human dendritic cell maturation and induce melanoma antigen-specific CD4 and CD8 T-cell responses, thereby enhancing antitumor immunity. This study provides a promising strategy by combining γδ-T exosomes and PDT for photoimmunotherapy, thereby expanding the clinical applications of γδ-T exosome therapy for cancer patients.
黑色素瘤是最具侵袭性的皮肤癌类型。传统的化疗和放疗效果有限，且会导致全身副作用。光动力疗法（PDT）是一种基于光敏剂产生活性氧（ROS）以根除肿瘤细胞的光响应性癌症治疗方法。我们之前的研究表明，源自人γδ-T细胞的外泌体（γδ-T外泌体）可以控制与爱泼斯坦-巴尔病毒相关的肿瘤。在此，我们通过γδ-T外泌体与负载氯卟啉e6（Ce6）的脂质体的膜融合，将γδ-T外泌体与PDT相结合用于靶向光免疫治疗。杂合外泌体上的功能性表面蛋白，如CCR5和PD-1，介导了杂合外泌体与黑色素瘤组织的特异性结合。来自γδ-T外泌体的细胞溶解分子，如颗粒酶A、颗粒酶B、穿孔素和颗粒溶素，可诱导癌细胞特异性凋亡而不损害正常细胞。在光照射下，黑色素瘤细胞内产生的ROS与细胞溶解分子协同作用，诱导凋亡并促进免疫原性癌细胞死亡（ICD）。随后释放的损伤相关分子模式（DAMPs）可刺激人树突状细胞成熟，并诱导黑色素瘤抗原特异性CD4和CD8 T细胞反应，从而增强抗肿瘤免疫力。本研究通过将γδ-T外泌体与PDT相结合用于光免疫治疗，提供了一种有前景的策略，从而扩大了γδ-T外泌体疗法在癌症患者中的临床应用。
