Table 1 The role and function of efficacious cytokines at immune paths of NK cell therapy

IL-2

First FDA-approved cytokine promotes NK cells in vivo homeostasis, cytotoxicity, and proliferation

Repeated injections are well tolerated at low doses and produce LAK cells

Activation of T_reg

Life-threatening toxicity at high doses, including vascular leakage and organ injury

Super-2 (mutant form): increased affinity to IL-2Rβ, independent of IL-2Rα (CD25), reversed NK cell’s anergic state, promoted NK cell proliferation, and the expansion of cytotoxic T cells but not T_reg

[5, 8, 75]

IL-15

Substantial role in homeostasis and cytotoxicity of NK cells. Activate both immature and mature NK cells and memory CD8⁺ T cells without activating T_reg

In combination with IL-12 and IL-18 generate CIML NK cells

Fever, thrombocytopenia, and hypotension

dsNKG2D-IL-15: protein fusion and enhanced NK cell-targeting ability through increasing tumor growth-suppressing capacity

IL-15 (heterodimeric): chimeric protein fusion of IL-15 with IL-15Rα promote NK cells and represses tumors

[37, 45, 51, 75, 157]

IL-12

Stimulate the NK cell production of cytokines (particularly IFN-γ)

In combination with IL-15 and IL-18 generate CIML NK cells

Robust NK cell anti-tumor immunity by enhanced cytotoxicity effect

–

NHS-IL12: Modified cytokine (IL-12⁺ tumor necrosis-targeting human IgG1), prolonged half-life, reduced side effects, and activating splenic and tumor-infiltrating NK

[37, 45, 51]

IL-18

Increase NK cell activity and differentiation and induce memory NK cell formation

NK cells survive through C-apoptosis inhibitor 2 and TNF receptor-associated factor 1 pathway

In combination with IL-12 and IL-15 generate CIML NK cells

–

–

[37, 45, 54, 158]

IL-21

Enhance IFN-γ production and cytotoxic functions

Limited viability support limit expansion and start apoptosis of NK cells

–

–

[137, 146, 159]