IL-2-based cancer immunotherapies have evolved significantly, with a focus on improving safety and efficacy. IL-2, a potent cytokine, is crucial for T cell expansion and regulatory T cell function. However, high-dose IL-2 therapy is limited by its short half-life and severe side effects, including capillary leak syndrome (CLS). To address these issues, various engineered IL-2 variants and delivery strategies have been developed. These include PEGylation to extend half-life, fusion with antibodies to target specific cells, and combination with immune checkpoint inhibitors like anti-PD-1. IL-2 variants such as BEMPEG and SAR444245 show reduced binding to IL-2Rα, favoring signaling through the intermediate affinity IL-2Rβγc, which is expressed on effector T cells and NK cells. These variants demonstrate improved safety profiles and enhanced anti-tumor activity. Additionally, oncolytic viruses expressing IL-2 have shown promise in preclinical models. Despite these advancements, challenges remain in translating these therapies into clinical success due to toxicity and efficacy limitations. Ongoing research aims to optimize delivery methods and combination strategies to enhance the therapeutic potential of IL-2 in cancer treatment.IL-2-based cancer immunotherapies have evolved significantly, with a focus on improving safety and efficacy. IL-2, a potent cytokine, is crucial for T cell expansion and regulatory T cell function. However, high-dose IL-2 therapy is limited by its short half-life and severe side effects, including capillary leak syndrome (CLS). To address these issues, various engineered IL-2 variants and delivery strategies have been developed. These include PEGylation to extend half-life, fusion with antibodies to target specific cells, and combination with immune checkpoint inhibitors like anti-PD-1. IL-2 variants such as BEMPEG and SAR444245 show reduced binding to IL-2Rα, favoring signaling through the intermediate affinity IL-2Rβγc, which is expressed on effector T cells and NK cells. These variants demonstrate improved safety profiles and enhanced anti-tumor activity. Additionally, oncolytic viruses expressing IL-2 have shown promise in preclinical models. Despite these advancements, challenges remain in translating these therapies into clinical success due to toxicity and efficacy limitations. Ongoing research aims to optimize delivery methods and combination strategies to enhance the therapeutic potential of IL-2 in cancer treatment.