Mechanisms of Cytokines Affecting the Effect of CAR-NK

Cytokines are key regulators of the immune system and have a profound impact on the efficacy of CAR-NK (chimeric antigen receptor-natural killer) cell therapy. These signaling molecules play an important role in regulating the activation, proliferation, persistence, and cytotoxic function of CAR-NK cells, making them a key factor in the success of immunotherapy.

Cytokines such as interleukin 2 (IL-2), interleukin 15 (IL-15), and interleukin 21 (IL-21) are essential for the activation and expansion of NK cells. IL-2 and IL-15 are particularly important because they bind to receptors on NK cells, initiating signaling pathways that lead to increased cell division, improved survival, and enhanced cytotoxic activity. IL-15 is particularly noteworthy for its role in maintaining the NK cell population, making it a cornerstone in maintaining the effectiveness of CAR-NK cells after infusion. IL-21 also promotes NK cell activation by enhancing the expression of activating receptors such as NKG2D and NKp46, which are critical for recognizing and killing tumor cells.

Cytokines also directly enhance the cytotoxic function of CAR-NK cells. For example, IL-12 stimulates NK cells to produce interferon-γ (IFN-γ), a cytokine that enhances the ability of NK cells to lyse tumor cells and modulate the tumor microenvironment to be more favorable for immune responses. In addition, cytokines such as IL-21 can increase the expression of key activating receptors on NK cells, further enhancing their ability to target and destroy cancer cells.

In addition, Cytokines such as IL-15 are involved in inducing a memory-like phenotype of NK cells, which is characterized by prolonged survival and enhanced responsiveness upon re-exposure to antigen. This “memory” property is beneficial for long-term tumor control, as CAR-NK cells with memory-like properties can persist in vivo and provide sustained anti-tumor activity.

On the other hand, certain cytokines in the tumor microenvironment, such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), can inhibit NK cell activity. These cytokines can inhibit NK cell proliferation, reduce the expression of activating receptors, and weaken their cytotoxic function, posing a major challenge to the efficacy of CAR-NK therapy.

Together, cytokines play a key role in determining the success of CAR-NK cell therapy by regulating NK cell activation, proliferation, cytotoxicity, and persistence. Although proinflammatory cytokines enhance the therapeutic potential of CAR-NK cells, immunosuppressive cytokines in the tumor microenvironment may weaken their effectiveness. Strategies to optimize cytokine support while counteracting inhibitory signals are essential to maximize the therapeutic effect of CAR-NK cell therapy.

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Reference

[1] Wenkang Wang et al., Cell Death Discovery 2024 (https://doi.org/10.1038/s41420-024-01815-9)