The CBS-CXCL10 signaling axis supports tumor progression by driving immune suppression within the tumor microenvironment

Cystathionine beta-synthase (CBS), a key enzyme in the transsulfuration pathway, is overexpressed in cancer cells and promotes tumor progression in part through hydrogen sulfide-mediated metabolic reprogramming. However, its role in shaping the tumor microenvironment and antitumor immunity is not well defined. Here, we show that CBS is highly expressed in head and neck cancer (HNC) tissues and cell lines, and that CBS knockdown slows tumor growth while enhancing antitumor immune responses in orthotopic syngeneic mouse models. Mechanistically, CBS silencing downregulates PSAT1 transcription, a key enzyme in the serine biosynthesis pathway, leading to intracellular serine depletion, DNA damage, and increased oxidative stress. These stress responses activate the cytosolic DNA-sensing pathway, triggering the cGAS-STING axis with phosphorylation and nuclear translocation of IRF3 and subsequent transcription of the chemokine CXCL10. Elevated CXCL10 functions as a potent chemoattractant for cytotoxic T cells, enriching the tumor microenvironment with effector lymphocytes and enhancing tumor control in vivo. Immunophenotyping and functional assays support a reprogrammed microenvironment consistent with heightened antitumor immunity upon CBS knockdown. Importantly, these effects are observed in an immunocompetent, orthotopic model, suggesting that CBS-driven signaling intersects with innate DNA sensing to modulate adaptive immunity in HNC. Collectively, these findings reveal a previously unrecognized immunomodulatory role for CBS in HNC and identify CBS as a potential metabolic-immune-target to augment tumor-reactive immunity and improve immunotherapy outcomes