PO.IM02.05 · 免疫学
CBS-CXCL10信号轴通过在肿瘤微环境中驱动免疫抑制来支持肿瘤进展
The CBS-CXCL10 signaling axis supports tumor progression by driving immune suppression within the tumor microenvironment
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胱硫醚β-合酶（CBS）是转硫途径中的关键酶，在癌细胞中过表达，部分通过硫化氢介导的代谢重编程促进肿瘤进展。然而，其在塑造肿瘤微环境和抗肿瘤免疫中的作用尚不明确。在此，我们发现CBS在头颈癌（HNC）组织和细胞系中高表达，并且在原位同基因小鼠模型中，CBS敲低减缓肿瘤生长，同时增强抗肿瘤免疫应答。在机制上，CBS沉默下调丝氨酸生物合成途径中的关键酶PSAT1的转录，导致细胞内丝氨酸耗竭、DNA损伤和氧化应激增加。这些应激反应激活胞质DNA感应途径，触发cGAS-STING轴，伴随IRF3的磷酸化和核转位，进而转录趋化因子CXCL10。CXCL10升高作为细胞毒性T细胞的强效趋化因子，使肿瘤微环境富集效应淋巴细胞，并增强体内的肿瘤控制。免疫表型分析和功能实验支持CBS敲低后微环境被重编程，与增强的抗肿瘤免疫相一致。重要的是，这些效应在免疫健全的原位模型中观察到，提示CBS驱动的信号与固有DNA感应交汇，从而在HNC中调节适应性免疫。总之，这些发现揭示了CBS在HNC中先前未被认识的免疫调节作用，并将CBS确定为一个潜在的代谢-免疫靶点，可增强肿瘤反应性免疫并改善免疫治疗结局。
查看英文原文 English abstract
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
利益披露 Disclosure
Y. Teng, None.