Integrated profiling of RUNX3 in intratumoral NK cells activity through bulk and single-cell transcriptomic analysis

Background: Natural killer (NK) cells are core components of innate antitumor immunity, the dysfunction of NK cells in the tumor microenvironment is a major obstacle to the antitumor efficacy. Runt-related transcription factor 3 (RUNX3) acts as a critical tumor suppressor and regulates immune cell function, while its biological role in NK cells remains largely unexplored. Herein, we investigated the interaction between RUNX3 and NK cells in tumor microenvironment. Methods: experiments were further performed to validate RUNX3's role in regulating NK cell functions. Results: T cells. scRNA-seq indicated RUNX3 enrichment in intratumoral NK cells, and differential genes of RUNX3 were enriched in the MAPK signaling pathway. Pseudotime trajectory analysis indicated RUNX3 participated in NK cell differentiation. Moreover, RUNX3 overexpression enhanced NK cell viability, chemotactic capacity, cytotoxicity against tumor cells, and secretion of pro-inflammatory cytokines and granzyme B, while upregulating NK cell activation receptors. Conclusion: Our findings identify RUNX3 as a key regulator of NK cell-mediated antitumor immunity in LUAD and LIHC, providing a novel molecular target for enhancing innate immune surveillance and developing targeted immunotherapies for the aggressive malignancies.