近日，美国哥伦比亚大学程柯及其小组提出了工程T细胞双特异性外泌体激活剂靶向免疫检查点抑制剂抵抗转移性黑色素瘤。这一研究成果于2026年1月5日发表在国际顶尖学术期刊《自然—生物技术》上。

在这里，研究小组开发了一种可吸入的外泌体系统，能够共同显示两种抑制配体，并将其应用于治疗ICI抵抗性黑色素瘤的肺转移。由于这种情况下的免疫排斥通常是由Wnt/β-catenin信号传导介导的，研究小组利用Alix分选结构域串联显示PD-1和FZD8，以阻断PD-L1和Wnt7b，这两个基因在ICI耐药黑色素瘤中过表达。这项技术被称为T细胞的双特异性外泌体激活剂（BEAT），可以使两种蛋白质在外泌体表面均匀地1:1共同展示。研究组发现BEAT同时招募和激活CD8T细胞重编程TME，在ICI抗性黑色素瘤小鼠模型中产生较强的抗肿瘤活性。在体内，吸入式BEAT优于靶向PD-L1和Wnt7b的联联双抗体。这种串联蛋白展示的方法可能适用于多种ICI耐药癌症。

研究人员表示，使用免疫检查点抑制剂（ICIs）进行癌症免疫治疗通常受到免疫抑制肿瘤微环境（TME）的限制。同时靶向TME和免疫检查点是解决这一限制的一种有希望的方法。

附：英文原文

Title: Engineering bispecific exosome activators of T cells to target immune checkpoint inhibitor-resistant metastatic melanoma

Author: Liu, Shuo, Liu, Mengrui, Wang, Zhenzhen, Hu, Shiqi, Zhang, Kaiyue, Lu, Chao, Cheng, Xiao, Shen, Ming, Bi, Jianing, Zhu, Dashuai, Cheng, Ke

Issue&Volume: 2026-01-05

Abstract: Cancer immunotherapy with immune checkpoint inhibitors (ICIs) is often limited by an immunosuppressive tumor microenvironment (TME). Simultaneous targeting of the TME and immune checkpoints is a promising approach to address this limitation. Here we develop an inhalable exosome system that enables co-display of two inhibitory ligands and apply it to treat lung metastases of ICI-resistant melanoma. As immune exclusion in this context is often mediated by Wnt/β-catenin signaling, we harnessed the Alix sorting domain for tandem display of PD-1 and FZD8 to block PD-L1 and Wnt7b, which is overexpressed in ICI-resistant melanoma. This technology, called bispecific exosome activator of T cells (BEAT), enables uniform 1:1 co-display of two proteins on the exosome surface. We show that BEAT concurrently recruits and activates CD8 T cells to reprogram the TME, yielding robust antitumor activity in ICI-resistant melanoma mouse models. Inhaled BEAT outperforms linked dual antibody targeting PD-L1 and Wnt7b in vivo. This approach to tandem protein display may be applicable to diverse ICI-resistant cancers.

DOI: 10.1038/s41587-025-02890-8

Source: https://www.nature.com/articles/s41587-025-02890-8