IL-2Rα-biased agonist enhances antitumor immunity by invigorating tumor-infiltrating CD25+CD8+ T cells

Nat Cancer. 2023 Sep;4(9):1309-1325. doi: 10.1038/s43018-023-00612-0. Epub 2023 Aug 7.


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-2). 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-2, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes* / pathology
  • Interleukin-2 / pharmacology
  • Interleukin-2 Receptor alpha Subunit
  • Mice
  • Neoplasms* / drug therapy
  • Programmed Cell Death 1 Receptor


  • Interleukin-2 Receptor alpha Subunit
  • Interleukin-2
  • Programmed Cell Death 1 Receptor