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.