High-dose IL-2 may preferentially target high-affinity IL-2R present on Treg cells and recently activated effector T cells. Recent strategies to target IL-2 signaling for cancer therapy include mutant IL-2 with affinity toward different IL-2R chains (alpha, or beta and gamma). Mutant IL-2 with affinity toward IL-2Rα is used to target Treg cells or recently activated effector T cells. Meanwhile, mutant IL-2 with affinity toward IL-2Rβ or IL-2Rγ subunits, rather than IL-2Rα, has been shown to target CD8⁺ memory T cells and NK cells with reduced binding to Treg cells. Combination of IL-2 therapy with various anti–IL-2 mAbs also differentially stimulates specific immune cell subsets. IL-2–based fusion proteins bound to antigen-specific antibodies (immunocytokines) allow for targeted delivery of IL-2 to cells/tissues expressing a protein of interest. PD-1–laIL-2, developed by Ren et al. (20), consists of low-affinity IL-2 (laIL-2) linked to an anti–PD-1 antibody. PD-1–laIL-2 selectively reactivates intratumoral PD-1⁺TIM-3⁺CD8⁺ T cells to enhance antitumor activity. In the future, additional IL-2–based fusion proteins may be engineered to target certain cells of interest in various disease contexts.