Harnessing IL-2 for immunotherapy against cancer and chronic infection: a historical perspective and emerging trends

IL-2 therapy, which enhances the function of CD8 + T cells, was initially employed as the cornerstone of immunotherapy against cancer. However, the impact of this therapy extends beyond CD8 + T cells to cells expressing IL-2R, such as endothelial cells and regulatory T cells (Tregs), resulting in various side effects. Consequently, IL-2 therapy has taken a step back from the forefront of treatment. Immune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1 antibodies and CTLA-4 antibodies, are used because of their durable therapeutic responses and the reduced incidence of side effects. Nevertheless, only a small fraction of cancer patients respond to ICIs, and research on IL-2 as a combination treatment to improve the efficacy of these ICIs is ongoing. To mitigate side effects, efforts have focused on developing IL-2 variants that do not strongly bind to cells expressing IL-2Rα and favor signaling through IL-2Rβγ. However, recent studies have suggested that, in the context of persistent antigen stimulation models, effective stimulation of antigen-specific exhausted CD8 + T cells in combination with PD-1 inhibitors requires either 1) binding to IL-2Rα or 2) delivery via a fusion with PD-1. This review explores the historical context of IL-2 as an immunotherapeutic agent and discusses future directions for its use in cancer immunotherapy. Interleukin-2 is crucial for combating cancer, but its use is restricted due to severe side effects. This article reviews the development of IL-2 therapy and how it affects CD8 T cells—important immune cells that can become dysfunctional or “exhausted.” To reduce the unwanted effects, researchers have been trying to create a safer version of IL-2 that avoids targeting certain immune and body cells that contribute to these side effects. Recent studies, however, indicate that using the original form of IL-2 or specifically targeting exhausted CD8 T cells with a marker called PD-1 could be more effective in fighting tumors. Additionally, combining IL-2 therapy with PD-1 blockade can enhance T cells response to cancer. These findings suggest a promising future for personalized and effective cancer treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.