Abstract B021: CBS fosters an immunosuppressive tumor microenvironment through regulation of the cGAS-STING pathway

Abstract Head and neck cancer (HNC) is a worldwide public health problem and cancer patients have limited treatment options. Cystathionine β-synthase (CBS) overexpression promotes tumor progression by elevating hydrogen sulfide production and inducing metabolic reprogramming in cancer cells. However, its role in modulating the tumor microenvironment remains insufficiently defined. In this study, we demonstrate that CBS is highly expressed in HNC. CBS knockdown not only impairs tumor growth but also enhances antitumor immune responses. Mechanistically, silencing CBS downregulates PSAT1 transcription, a key enzyme in the serine biosynthesis pathway, leading to serine-related DNA damage and oxidative stress. These stress responses trigger activation of the cGAS-STING pathway through cytosolic DNA accumulation, promoting IRF3 phosphorylation and nuclear translocation, ultimately inducing CXCL10 transcription. Elevated CXCL10 functions as a chemoattractant, recruiting cytotoxic T cells to the tumor microenvironment, thereby augmenting antitumor immunity in an orthotopic syngeneic mouse model of HNSCC with CBS knockdown. Together, these findings reveal a previously unrecognized immunomodulatory role for CBS and highlight its potential as a therapeutic target to boost tumor-reactive immune responses and improve the efficacy of cancer immunotherapy. Citation Format: Fanghui Chen, Jianqiang Yang, Fan Yang, YONG TENG. CBS fosters an immunosuppressive tumor microenvironment through regulation of the cGAS-STING pathway [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B021.