Advances in IL-2-based cancer immunotherapy and the synergistic role of stem-like CD8+ T cells in IL-2 and PD-1 combination therapy.

IL-2 is a pleiotropic cytokine that plays a central role in the activation and proliferation of cytotoxic lymphocytes and regulatory T cells. Since its discovery in 1976 as a T-cell growth factor and its subsequent U.S. FDA approval for metastatic renal cell carcinoma and melanoma, IL-2 has represented a landmark in cancer immunotherapy. However, high-dose (HD) IL-2 therapy is associated with substantial toxicities, including vascular leak syndrome. Recent advances in structural and receptor biology have clarified the molecular mechanisms underlying IL-2's dual immunostimulatory and immunoregulatory effects. These discoveries have enabled the design of next-generation IL-2 variants (IL-2v) with improved pharmacokinetics, receptor selectivity, and safety profiles. Importantly, PD-1+ TCF-1+ stem-like CD8+ T cells have recently been identified as a key population sustaining long-term antitumor immunity. TCF-1 is a transcription factor associated with a less differentiated, self-renewing state and marks this progenitor-exhausted subset. By contrast, terminally exhausted T cells exhibit a highly differentiated, poorly proliferative state and limited capacity for functional reinvigoration, whereas progenitor-exhausted cells retain stem-like properties, self-renewal capacity, and responsiveness to therapy. Furthermore, these cells respond robustly to IL-2 and are central mediators of the synergy observed between IL-2 signaling and PD-1 blockade. Mechanistically, PD-1 inhibition releases inhibitory constraints, while IL-2 provides a potent STAT5-driven proliferative and differentiation signal that expands the stem-like CD8+ T-cell pool and generates functional effector CD8+ T cells. This review summarizes IL-2 biology, the limitations of high-dose IL-2 (HD IL-2) therapy, and emerging strategies, including CD25- or CD122-biased IL-2 variants, tumor-targeted IL-2 prodrugs, and IL-2-based combination therapies designed to harness IL-2's antitumor potential while minimizing systemic toxicity, with particular emphasis on the role of stem-like CD8+ T cells as key mediators of therapeutic efficacy.