Natural killer (NK) cells are key effectors in cancer immunotherapy, offering potent cytotoxicity and the advantage of allogeneic use. However, clinical translation of NK cell–based therapies is hampered by inefficient ex vivo expansion and limited in vivo persistence. While interleukin-2 (IL-2) is commonly used to support NK cells, it also expands regulatory T cells and can induce activation-induced cell death. In contrast, interleukin-21 (IL-21) selectively promotes NK cell proliferation and function without these drawbacks, making it a promising alternative cytokine. However, its short in vivo half-life limits sustained biological activity.
To address this, we engineered IL-21 Fc, a fusion protein linking IL-21 to the Fc region of human IgG to prolong its half-life. IL-21 Fc treatment of peripheral blood mononuclear cells (PBMCs) significantly enhanced NK cell proliferation and delayed apoptosis compared to IL-2, while preserving cytotoxic function and activation marker expression. In tumor-bearing mouse models, IL-21 Fc administration improved NK cell–mediated tumor control and was associated with increased NK cell persistence.
These findings suggest that IL-21 Fc is an effective cytokine platform to overcome key barriers in NK cell–based immunotherapy by supporting robust expansion and sustained function both in vitro and in vivo.