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

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Natural killer (NK) cells are crucial for innate antitumor immunity, but their function is often compromised within the tumor microenvironment.
• Runt-related transcription factor 3 (RUNX3) is a known tumor suppressor, yet its specific role in NK cell function and antitumor immunity remains largely uncharacterized.

Purpose of the Study:

• To investigate the role of RUNX3 in NK cell function within the tumor microenvironment.
• To explore RUNX3's potential as a therapeutic target for enhancing antitumor immunity.

Main Methods:

• Utilized The Cancer Genome Atlas (TCGA) for genetic alteration analysis of RUNX3.
• Employed TIMER and GEPIA for assessing RUNX3 correlation with immune cell infiltration.
• Conducted single-cell RNA sequencing (scRNA-seq) to analyze RUNX3 expression and NK cell differentiation.
• Performed in vitro experiments to validate RUNX3's impact on NK cell functions.

Main Results:

• RUNX3 expression was significantly downregulated in lung adenocarcinoma and hepatocellular carcinoma, correlating with poor prognosis.
• RUNX3 positively associated with the infiltration of NK cells and CD8+ T cells.
• scRNA-seq revealed RUNX3 enrichment in intratumoral NK cells, involvement in differentiation, and regulation of MAPK signaling.
• Overexpression of RUNX3 boosted NK cell viability, cytotoxicity, and cytokine secretion.

Conclusions:

• RUNX3 is identified as a critical regulator of NK cell-mediated antitumor immunity in lung and liver cancers.
• RUNX3 represents a promising molecular target for improving innate immune surveillance and developing novel immunotherapies for aggressive cancers.