Sun Yixuan, Zhou Yang, Peng Qihua, Zhou Wanzhen, Li Xiao, Wang Ruiwen, Yin Yifan, Huang Huixian, Yao Hongfei, Li Qing, Zhang Xueli, Hu Lipeng, Jiang Shuheng, Zhang Zhigang, Li Dongxue, Zhu Xiaolu, Teng Yincheng
Department of Gynecology and Obstetrics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, P.R. China.
Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P.R. China.
Int J Biol Sci. 2025 Jan 20;21(3):1361-1377. doi: 10.7150/ijbs.105572. eCollection 2025.
Cervical cancer remains the most prevalent gynecological malignant disease. Reprogramming tumor immune metabolism stands out as a novel promising therapeutic target. Here, we identified serine incorporator 2 (SERINC2) as a critical gene which highly expressed in cervical cancer and negatively correlated with clinical outcomes. Through functional assays, SERINC2 was determined to play a pro-tumoral role both and . Besides, the growth of cervical cancer cells was found to be largely dependent on serine in a manner influenced by SERINC2. As a serine transport associated protein, SERINC2 knockdown significantly reduced cervical cancer cells' intracellular serine level and altered the serine-associated-lipid metabolism. Immune infiltration analysis revealed that SERINC2 was negatively associated with CD8 T cell infiltration and function. More importantly, we demonstrated a competitive relation between cancer cells and immune cells brought about by SERINC2. Mechanistically, cancer cells SERINC2 preferentially competed for micro-environmental serine over CD8 T cells and rendered T cell exhaustion. Overall, SERINC2 remodels cancer development and serine metabolism in the tumor immune microenvironment (TIME), establishing an immunosuppressive and pro-tumoral milieu.
宫颈癌仍然是最常见的妇科恶性疾病。肿瘤免疫代谢重编程作为一个新的有前景的治疗靶点而备受关注。在此，我们鉴定出丝氨酸整合蛋白2（SERINC2）是一个在宫颈癌中高表达且与临床预后呈负相关的关键基因。通过功能分析，确定SERINC2在[具体方面1]和[具体方面2]均发挥促肿瘤作用。此外，发现宫颈癌细胞的生长在很大程度上依赖丝氨酸，且这种依赖受SERINC2影响。作为一种与丝氨酸转运相关的蛋白，SERINC2基因敲低显著降低宫颈癌细胞内的丝氨酸水平，并改变与丝氨酸相关的脂质代谢。免疫浸润分析显示，SERINC2与CD8 T细胞浸润及功能呈负相关。更重要的是，我们证明了SERINC2导致癌细胞与免疫细胞之间存在竞争关系。机制上，癌细胞中的SERINC2比CD8 T细胞更优先竞争微环境中的丝氨酸，从而导致T细胞耗竭。总体而言，SERINC2重塑肿瘤免疫微环境（TIME）中的肿瘤发展和丝氨酸代谢，建立一个免疫抑制和促肿瘤的微环境。
