GATA1-mediated Notch signaling augment antitumor immunity of CD11b+CD27- natural killer cells maturation via BCL9/β-catenin signal.

The maturation process of natural killer (NK) cells is integral to their antitumor immune response. Despite the diverse effector properties exhibited during differentiation, targeting the fate of NK cells for immunotherapy remains challenging. Here, we demonstrate that deficiency of B cell lymphoma 9 (BCL9) induces transient expression of GATA1 in CD11b⁺ CD27^- NK cells upon activation of Notch and interleukin-18 receptor 1 (IL-18R1) signaling, which are crucial for their maturation and antitumor activity. Conversely, blocking Notch signaling impairs NK cell development and antitumor function. NK-specific Bcl9-deficiency enhances B16F10 tumor killing in vivo. Our findings underscore the intricate network interactions among transcription factors, signal transduction pathways in development, and cytokines modulated by BCL9 deficiency. Targeting BCL9 emerges as a promising strategy for melanoma therapy, bolstering NK cell maturation and cytotoxicity, and overcoming challenges in NK cell-based immunotherapies.