使用免疫检查点抑制剂（ICIs）的策略彻底改变了癌症治疗，取得了显著的临床成果。然而，某些癌症类型和患者人口统计学仍面临独特的挑战。因此，必须研究涉及ICIs的联合治疗，以增强治疗效果。核苷酸衍生物cordycepin是由腺嘌呤和戊糖组成的，对于治疗炎症和癌症具有巨大的潜力。我们最近的研究表明，cordycepin与抗CD47抗体的联合治疗显著抑制肿瘤生长并延长了负担肿瘤的小鼠寿命。在本研究中，我们展示了cordycepin与CTLA-4阻断的联合对抑制肿瘤生长具有深远影响。我们利用MC38和CT26肿瘤模型评估了cordycepin、CTLA-4阻断以及它们的联合方法的治疗效果。流式细胞仪结果揭示，当cordycepin与CTLA-4阻断联合时，显著增加了肿瘤浸润的CD8+T细胞数量，同时减少了肿瘤微环境（TME）中Foxp3+T调节细胞的比例。此外，我们采用单细胞分析研究了抗CTLA-4和cordycepin联合治疗对TME的重构。我们观察到，对负担肿瘤的小鼠，该联合治疗方案显著抑制了肿瘤生长，极大延长了生存期。我们的数据还表明，与其他所有组相比，联合治疗组中效应器CD8+T细胞的比例增加，而耗竭的CD8+T细胞在联合组中减少。总之，我们的研究结果支持cordycepin与CTLA-4阻断的联合能够改变CD8+T细胞的效应和衰竭状态，从而增强TME中CD8+T细胞介导的反肿瘤免疫力。综上所述，我们的研究成功建立了应用cordycepin和CTLA-4阻断的联合治疗策略。该策略对抗癌症产生了显著的协同效应，凸显了它在癌症治疗中的重要性。版权所有 © 2023 Elsevier B.V. 发布。

The strategy of using immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, leading to remarkable clinical outcomes. However, certain cancer types and patient demographics continue to face unique challenges. As a result, it is vital to investigate combination therapies that involve ICIs to boost therapeutic efficacy. Cordycepin, an adenosine derivative composed of adenine and pentose, holds immense promise for treating inflammation and cancer. Our recent research has demonstrated that the combined treatment of cordycepin and the anti-CD47 antibody significantly curtails tumor growth and extends the lifespan of tumor-bearing mice. In the current study, we showed that the combination of cordycepin and CTLA-4 blockade had a profound impact on suppressing tumor growth. We utilized the MC38 and CT26 tumor models to evaluate the therapeutic effect of cordycepin, CTLA-4 blockade, and their combined approach. Flow cytometry results unveiled that cordycepin, when combined with CTLA-4 blockade, considerably augmented the presence of tumor-infiltrating CD8+T cells and diminished the population of Foxp3+Tregs within the tumor microenvironment (TME). Additionally, we employed single-cell analysis to examine the TME's reconfiguration upon the combined treatment of anti-CTLA-4 and cordycepin. We observed a significant impact on inhibiting tumor growth and substantially extended survival in tumor-bearing mice. Our data also demonstrated an increased proportion of effector CD8+T cells in the combined treatment group compared to all other groups, while exhausted CD8+T cells diminished in the combined group compared to the anti-CTLA-4 treatment alone. In conclusion, our findings supported the idea that combining cordycepin and CTLA-4 blockade could modify the effector and exhaustion status of CD8+T cells, thereby bolstering CD8+T-cell-mediated anti-tumor immunity in the TME. Collectively, our current study successfully established a combination therapeutic strategy utilizing cordycepin and CTLA-4 blockade. This strategy demonstrated a significant synergistic effect against cancer, highlighting its importance in cancer treatment.Copyright © 2023. Published by Elsevier B.V.