iTeos疗法的Erica Houthuys小组的研究显示，抑制ENT1可缓解细胞内腺苷介导的T癌症中的细胞抑制。该研究于2025年5月12日发表于国际一流学术期刊《自然—免疫学》杂志上。

小组发现腺苷抑制抗癌T被激活的T通过平衡核苷转运蛋白1 （ENT1）和抑制从头合成嘧啶核苷酸。课题组发现EOS301984是一种有效的ENT1拮抗剂，可以恢复激活T细胞在富含腺苷的环境中，导致记忆T细胞和功能性人肿瘤浸润淋巴细胞体外扩增增加。EOS301984联合抗PD-1可协同控制三阴性乳腺癌人源化小鼠模型的肿瘤生长。因此，抑制ENT1可通过恢复T被腺苷抑制的细胞。

据悉，由于肿瘤内免疫抑制代谢物（如腺苷）的积累等因素，免疫检查点阻断对癌症治疗的益处仅限于患者亚群。腺苷生成和信号传导的药理抑制是临床研究的一个活跃领域，但只有有限的临床益处被报道。

附：英文原文

Title: Inhibition of ENT1 relieves intracellular adenosine-mediated Tcell suppression in cancer

Author: Sanders, Theodore J., Nabel, Christopher S., Brouwer, Margreet, Hermant, Annelise L., Chaible, Lucas, Deglasse, Jean-Philippe, Rosewick, Nicolas, Pabois, Anglique, Cathou, Wilfried, Smets, Aurore, Deligny, Michael, Marchante, Joo, Dubray, Quentin, Letellier, Marie-Claire, Martinoli, Chiara, Marillier, Reece, De Henau, Olivier, McGrath, Yvonne, Vander Heiden, Matthew G., Houthuys, Erica

Issue&Volume: 2025-05-12

Abstract: The benefit of immune checkpoint blockade for cancer therapy is limited to subsets of patients because of factors including the accumulation of immunosuppressive metabolites, such as adenosine, within tumors. Pharmacological inhibition of adenosine generation and signaling is an active area of clinical investigation, but only limited clinical benefit has been reported. Here, we show that adenosine suppresses anti-cancer Tcell responses following uptake into activated Tcells by equilibrative nucleoside transporter 1 (ENT1) and inhibition of de novo pyrimidine nucleotide synthesis. We identify EOS301984 as a potent ENT1 antagonist that restores pyrimidine levels in activated Tcells in adenosine-rich environments, resulting in enhanced tumor cell killing by memory Tcells and increased ex vivo expansion of functional human tumor-infiltrating lymphocytes. A combination of EOS301984 with anti-PD-1 led to synergistic control of tumor growth in a humanized mouse model of triple-negative breast cancer. ENT1 inhibition, therefore, augments anti-cancer immune responses through the restoration of pyrimidine nucleotide synthesis in Tcells suppressed by adenosine.

DOI: 10.1038/s41590-025-02153-3

Source: https://www.nature.com/articles/s41590-025-02153-3