为了避免调节性T细胞的促进和血管毒性，在免疫肿瘤学中，大多数白介素-2受体β/白介素-2受体γ(IL-2Rβγ)偏向方法是使用的方法。然而，最近对这些IL-2激动剂的临床失望，对这一策略提出了质疑。在这里，我们展示了保留IL-2受体α (CD25) 活性的野生型(IL-2wt) 和IL-2Rβγ-衰减型 (IL-2α-偏向) 的激动剂与“非α”对应物 (IL-2nα) 相比，能够有效扩增肿瘤特异性CD8+ T细胞(TSTs)，并具有更好的抗肿瘤功效和安全性。机制上，TSTs同时表达升高的CD25和PD-1，并且对IL-2Rα的激动剂更容易受到刺激。此外，抗PD-1的抗肿瘤功效依赖于PD-1+CD25+ TSTs通过内源性IL-2-CD25信号传导的激活。在患有癌症的个体中，低IL-2标志物与抗PD-1治疗的非反应性相关。在小鼠模型中，IL-2α-偏向而不是IL-2nα，能够恢复IL-2标志物，并与抗PD-1协同作用来根除大型已建立的肿瘤。这些发现突显了CD25在基于IL-2的免疫疗法中的不可或缺作用，并为评估癌症个体中IL-2Rα-偏向激动剂提供了依据。© 2023. 作者（们）在Springer Nature America, Inc.独家许可下。

To avoid regulatory T cell promotion and vascular toxicity, the interleukin-2 receptor-β/interleukin-2 receptor-γ (IL-2Rβγ)-biased approach is used by most IL-2 analogs in immuno-oncology. However, recent clinical disappointments in these IL-2 agonists have questioned this strategy. Here we show that both wild-type (IL-2wt) and IL-2Rβγ-attenuated (IL-2α-bias) agonists that preserve IL-2Rα (CD25) activities can effectively expand tumor-specific CD8+ T cells (TSTs) and exhibit better antitumor efficacy and safety than the 'non-α' counterpart (IL-2nα). Mechanistically, TSTs coexpress elevated CD25 and PD-1 and are more susceptible to stimulation by IL-2Rα-proficient agonists. Moreover, the antitumor efficacy of anti-PD-1 depends on activation of PD-1+CD25+ TSTs through autocrine IL-2-CD25 signaling. In individuals with cancer, a low IL-2 signature correlates with non-responsiveness to anti-PD-1 treatment. In mouse models, IL-2α-bias, but not IL-2nα, restores the IL-2 signature and synergizes with anti-PD-1 to eradicate large established tumors. These findings underscore the indispensable function of CD25 in IL-2-based immunotherapy and provide rationales for evaluating IL-2Rα-biased agonists in individuals with cancer.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.