Liu Sifan, Zhang Nan, Ji Xu, Yang Shuyue, Zhao Zheng, Li Peng
Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory for Digestive Health, National Clinical Research Center of Digestive Diseases, Beijing Digestive Disease Center, Beijing, 100050, China.
Cell Death Dis. 2025 Jan 14;16(1):17. doi: 10.1038/s41419-024-07318-w.
Helicobacter pylori (H. pylori) infection is a well-established risk factor for gastric cancer, primarily due to its virulence factor, cytotoxin-associated gene A (CagA). Although PD-L1/PD-1-mediated immune evasion is critical in cancer development, the impact of CagA on PD-L1 regulation remains unclear. This study revealed that H. pylori CagA upregulated squalene epoxidase (SQLE) expression, a key enzyme in the cholesterol biosynthesis pathway. Elevated SQLE activity increased cellular palmitoyl-CoA levels, enhancing PD-L1 palmitoylation while decreasing its ubiquitination. This ultimately increases PD-L1 stability, suppressing T cell activity and facilitating immune evasion in gastric cancer. In summary, our findings highlight the crucial role of the CagA-SQLE-PD-L1 axis in gastric cancer progression, suggesting potential therapeutic strategies for targeting CagA-positive gastric cancer.
幽门螺杆菌（H. pylori）感染是胃癌公认的危险因素，主要归因于其毒力因子细胞毒素相关基因A（CagA）。尽管PD-L1/PD-1介导的免疫逃逸在癌症发展中至关重要，但CagA对PD-L1调节的影响仍不清楚。本研究表明，幽门螺杆菌CagA上调了角鲨烯环氧酶（SQLE）的表达，SQLE是胆固醇生物合成途径中的关键酶。升高的SQLE活性增加了细胞棕榈酰辅酶A水平，增强了PD-L1的棕榈酰化，同时降低了其泛素化。这最终增加了PD-L1的稳定性，抑制了T细胞活性，并促进了胃癌中的免疫逃逸。总之，我们的研究结果突出了CagA-SQLE-PD-L1轴在胃癌进展中的关键作用，为靶向CagA阳性胃癌提供了潜在的治疗策略。
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