Liu Rui, Li Hui-Fang, Jiang Qi, Shi Jun-Ge, Ruan Zi-Lun, Ren Peng, Li Yi-Nuo, Shu Hong-Bing, Li Shu
Department of Infectious Diseases, Medical Research Institute, Zhongnan Hospital of Wuhan University; Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences; Wuhan University, Wuhan, 430071, China.
EMBO J. 2025 Sep 8. doi: 10.1038/s44318-025-00557-3.
Inadequate antigen presentation by MHC-I in tumor microenvironment (TME) is a common immune escape mechanism. Here, we show that glycine decarboxylase (GLDC), a key enzyme in glycine metabolism, functions as an inhibitor of MHC-I expression in EGFR-activated tumor cells to induce immune escape by a mechanism independent of its enzymatic activity. Upon EGFR activation, GLDC is phosphorylated by SRC and subsequently translocated to the nucleus in human NSCLC cells. Nuclear GLDC sequesters STAT1 co-activator SMARCE1, inhibiting STAT1-dependent transcription of the inflammatory genes IRF1 and NLRC5. Further, GLDC recruits DNMT1 to the IRF1/NLRC5 promoter inducing DNA hypermethylation, suppressing transcription of downstream MHC-I genes. Inhibition of GLDC restores MHC-I levels in tumor cells, improves tumor-specific CD8 T cells functions in the TME, and rescues anti-tumor effects of PD-1 blockade therapy in mice. Our findings reveal a non-enzymatic nuclear function for GLDC in the suppression of MHC-I antigen presentation, suggesting new strategies for ICB-based combination immunotherapy.
肿瘤微环境（TME）中主要组织相容性复合体I类分子（MHC-I）介导的抗原呈递不足是一种常见的免疫逃逸机制。在此，我们发现甘氨酸代谢关键酶甘氨酸脱羧酶（GLDC）在表皮生长因子受体（EGFR）激活的肿瘤细胞中作为MHC-I表达的抑制剂，通过一种独立于其酶活性的机制诱导免疫逃逸。在EGFR激活后，GLDC被SRC磷酸化，随后在人非小细胞肺癌（NSCLC）细胞中易位至细胞核。细胞核内的GLDC隔离信号转导和转录激活因子1（STAT1）的共激活因子SMARCE1，抑制炎症基因干扰素调节因子1（IRF1）和NOD样受体家族CARD结构域蛋白5（NLRC5）依赖于STAT1的转录。此外，GLDC招募DNA甲基转移酶1（DNMT1）至IRF1/NLRC5启动子，诱导DNA高甲基化，抑制下游MHC-I基因的转录。抑制GLDC可恢复肿瘤细胞中MHC-I水平，改善TME中肿瘤特异性CD8 T细胞功能，并挽救小鼠中程序性死亡受体1（PD-1）阻断疗法的抗肿瘤作用。我们的研究结果揭示了GLDC在抑制MHC-I抗原呈递中的非酶促核功能，为基于免疫检查点阻断（ICB）的联合免疫治疗提出了新策略。
