Abstract B004: cGAS promote DLBCL survival through STAT3 and NF-κB signaling

Abstract The innate immunity cGAS–STING signaling has been extensively studied to boost lymphocytes infiltration for tumor inhibition/eradication. However, DLBCL cells often cope with, take advantage, and get addicted to chronic STAT3 and NF-κB inflammatory state for survival. Little is known whether this chronic STAT3 and NF-κB inflammatory state in DLBCL is cGAS or STING dependent. In this study, we examined the relationship of cGAS–STING and STAT3, NF-κB in DLBCL. Different from STING low or negative, cGAS is usually highly expressed in many cancer types. Here we discovered a cancer promoting role of cGAS in DLBCL through IL6-STAT3 and NF-κB signaling. Firstly, we showed that cGAS was highly expressed in both ABC and GCB subtypes of DLBCL. Secondly, we discovered that it is cGAS, not STING knockout, that induced cell cycle arrest, decreased proliferation rate and induced apoptosis in DLBC cell lines in vitro. cGAS knockout lead to decreased tumor growth in xenograft tumor models in vivo. Furthermore, data from TCGA show that cGAS was closely correlated with many tumor-promote genes. Pan-cancer analysis reveal that cGAS is overexpressed and predicts poor prognosis in many cancer types. Mechanically, it is cGAS, not STING knockout, that lead to downregulation of STAT3 and NF-κB signaling both in vitro and in vivo. Suppression of cGAS consequently deprives DLBCL from this pro-inflammatory niche for growth, which showed a therapeutic target in DLBCL treatment. Citation Format: Rui Wang, shuling Liu. cGAS promote DLBCL survival through STAT3 and NF-κB signaling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B004.