帕克癌症免疫治疗研究所Taha Merghoub小组在研究中取得进展。他们提出了血小板反应蛋白1–CD47信号传导促进癌症T细胞耗竭的发展。这一研究成果发表在2025年11月17日出版的国际学术期刊《自然—免疫学》上。

在这里，该课题组人员在人和小鼠肿瘤中发现了肿瘤浸润性衰竭CD8⁺ T细胞中CD47的上调。课题组揭示了细胞外基质蛋白血小板反应蛋白-1（TSP-1）参与CD47对T细胞促进衰竭的新作用。这种相互作用激活钙调磷酸酶-NFAT信号，诱导TOX和抑制受体的表达上调，并在肿瘤进展过程中损害效应物的功能。重要的是，破坏TSP-1-CD47轴可防止T细胞衰竭并增强肿瘤控制。他们的发现确定了促进T细胞功能障碍的新途径，并表明靶向TSP-1-CD47轴是增强T细胞免疫和免疫治疗疗效的有希望的策略。

据了解，T细胞衰竭是有效的癌症免疫治疗的主要障碍。尽管免疫检查点阻断可以重新激活耗尽的T细胞，但并非所有患者都能获得长期反应，部分原因是最终耗尽的T细胞的难治性。除了持续的抗原刺激，疲劳的环境驱动因素仍有待彻底表征。

附：英文原文

Title: Thrombospondin-1–CD47 signaling contributes to the development of T cell exhaustion in cancer

Author: Weng, Chien-Huan, Assouvie, Anais, Dong, Lauren, Beltra, Jean-Christophe, Budhu, Sadna, Mangarin, Levi, Marouf, Yacine, Morgado-Palacin, Lucia, Liu, Cailian, Monette, Sbastien, Khan, Jonathan F., Schulze, Isabell, Zamarin, Dmitriy, Hamadene, Linda, Samaan, Fadi, Hirschhorn, Daniel, Pourpe, Stephane, Schrder, David, Zappasodi, Roberta, Holland, Pamela M., Anandasabapathy, Niroshana, Wherry, E. John, Wolchok, Jedd D., Merghoub, Taha

Issue&Volume: 2025-11-17

Abstract: T cell exhaustion is a major barrier to effective cancer immunotherapy. Although immune checkpoint blockade can reinvigorate exhausted T cells, not all patients achieve long-term responses, partly due to the refractory nature of terminally exhausted T cells. Beyond persistent antigen stimulation, the environmental drivers of exhaustion remain to be thoroughly characterized. Here we identify CD47 upregulation in tumor-infiltrating exhausted CD8+ T cells in both human and murine tumors. We reveal a novel role for the extracellular matrix protein thrombospondin-1 (TSP-1) in engaging CD47 on T cells to promote exhaustion. This interaction activates calcineurin–NFAT signaling, inducing upregulation of TOX and expression of inhibitory receptors, and impairing effector function during tumor progression. Importantly, disrupting the TSP-1–CD47 axis prevents T cell exhaustion and enhances tumor control. Our findings identify a novel pathway promoting T cell dysfunction and suggest that targeting the TSP-1–CD47 axis is a promising strategy to enhance T cell immunity and immunotherapy efficacy.

DOI: 10.1038/s41590-025-02321-5

Source: https://www.nature.com/articles/s41590-025-02321-5