RAC2 inhibition enhances tumor sensitivity to NK cell-mediated cytotoxicity

• DOI: 10.1136/jitc-2024-010931
• Publication Date: 2025-05-02T11:46:44Z
• Authors: Hui Guo; Jie Hu; Zining Wang; Feifei Xu; Yongxiang Liu; Lei Cui; Huanling Zhang; Chunyuan Xie; Ruhui Yao; Huan Jin; Zixuan Guo; Tiantian Wang; Lin Li; Yanxun Lin; Xiaojuan Wang; Heping Li; Xiaojun Xia
• Keywords: Lymphokine-activated killer cell

Background Natural killer (NK) cells are recognized for their ability to kill tumor control, but often develop resistance evade NK cell-mediated cytotoxicity. Identification of molecular mechanisms by which from killing may offer novel therapeutic strategies potentiating NK-based cancer immunotherapy. Methods An in vitro tumor-NK cell co-culture system was employed identify the most significantly altered genes following interaction. The death rate exposure quantified using flow cytometry. EL4 and HCT116 models C57BL/6, BALB/c-nu, NOD/SCID mice were used evaluating growth differences induced Rac2 knockdown or knockout. cellular impact knockout on sensitivity cytotoxicity assessed quantitative PCR, immunofluorescence, mutation analysis. Results By screening expression levels Ras homology (Rho) GTPase family after with cells, we identified RAC2 as a key regulator among Rho members. Furthermore, human colorectal leads increased susceptibility xenograft model. Mechanistically, absence enhances facilitating cell–cell contact. Conclusions These findings indicate that inhibition substantially cytotoxicity, thereby providing potential target optimizing therapy.