Advances in IL-15-Based Cancer Immunotherapy and Divergent Immunological Effects of IL-2 and IL-15 Signaling via the Shared IL-2Rβγ Receptor.

Interleukin-15 (IL-15) has emerged as a central cytokine for next-generation cancer immunotherapy because of its unique ability to sustain the survival, proliferation, and cytotoxic function of memory CD8 T cells and natural killer (NK) cells without promoting the expansion of regulatory T cells (Treg). These properties make IL-15 particularly attractive for achieving durable antitumor immunity, especially in solid tumors where immune persistence remains a major limitation. Although IL-15 shares the same signal-transducing receptor subunits (IL-2R and the common chain) with interleukin-2 (IL-2), the two cytokines drive fundamentally different CD8 T-cell fates, a distinction that underlies their markedly divergent therapeutic profiles in cancer immunotherapy. In recent years, multiple IL-15-based therapeutic strategies including recombinant IL-15, and IL-15 immunocytokines have entered clinical evaluation, demonstrating potent immune activation with manageable toxicity profiles. Recent clinical progress includes the FDA approval of Nogapendekin alfa inbakicept (N-803), the first IL-15-based immunotherapy approved for cancer treatment, alongside the advancement of other IL-15 superagonists into Phase II trials and growing evidence that IL-15 can enhance the efficacy of immune checkpoint blockade and engineered adoptive cell therapies such as CAR-T cells, CAR-NK cells, T cells, and invariant NKT cells. Despite these advances, important challenges remain, including cytokine-associated toxicities, optimal delivery strategies, and the immunosuppressive tumor microenvironment. This review summarizes recent progress in IL-15-based cancer immunotherapy, integrates emerging insights into IL-2R-driven CD8 T-cell fate decisions, and discusses key opportunities and challenges for translating IL-15-mediated immune enhancement into durable clinical benefit.