Interleukin-15–mechanistic target of rapamycin signaling axis (IL-15–mTOR axis) (IL-15–mTOR axis)

The IL-15–mTOR axis is a fundamental signaling pathway governing the metabolic fitness, survival, and effector functions of Natural Killer (NK) cells (Viel et al., 2016, Nature Immunology). In the immunosuppressive environment of a tumor, Transforming Growth Factor-beta (TGF-β) acts as a major barrier to anti-tumor immunity by specifically inhibiting the mTOR (mechanistic target of rapamycin) pathway in NK cells, which leads to a state of metabolic starvation and functional exhaustion (Foltz et al., 2018, Journal of Immunology). Interleukin-15 (IL-15) serves as a critical counter-regulatory cytokine that, upon binding to its heterotrimeric receptor complex (IL-15Rα/β/γ), activates the PI3K/Akt/mTOR signaling cascade to restore cellular metabolism and cytotoxic activity (Mace et al., 2023, Frontiers in Immunology). Therapeutic interventions targeting this axis, such as IL-15 superagonists (e.g., N-803), are designed to provide sustained stimulatory signals that can override the inhibitory effects of TGF-β, thereby enhancing the efficacy of NK cell-based immunotherapies (Romee et al., 2016, Science Translational Medicine). This axis is currently a high-priority target in oncology for revitalizing the innate immune response against solid tumors and hematological malignancies (Knudson et al., 2020, Journal for ImmunoTherapy of Cancer).

Other names

IL-15/mTOR pathwayIL-15-mediated mTOR activationTGF-beta-suppressed NK cell signaling axisIL-15–mTOR axis in TGFβi NK cells under TGF-β exposure

Agonism of the Interleukin-15 receptor complex to trigger the JAK/STAT5 and PI3K/Akt/mTOR signaling pathways, thereby bypassing or overcoming TGF-beta-mediated metabolic and functional suppression in Natural Killer cells.