Ye Zhenzhen, Yi Jianfeng, Jiang Xiangyan, Shi Wengui, Xu Hao, Cao Hongtai, Qin Long, Liu Lixin, Wang Tianming, Ma Zhijian, Jiao Zuoyi
Department of General Surgery, The Second Clinical Medical School, The Second Hospital of Lanzhou University, Lanzhou University, Lanzhou, Gansu, 730000, China.
The First School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou, Gansu, 730000, China.
J Exp Clin Cancer Res. 2025 Jan 2;44(1):2. doi: 10.1186/s13046-024-03269-4.
Tumor-associated macrophages (TAMs), particularly M2-polarized TAMs, are significant contributors to tumor progression, immune evasion, and therapy resistance in gastric cancer (GC). Despite efforts to target TAM recruitment or depletion, clinical efficacy remains limited. Consequently, the identification of targets that specifically inhibit or reprogram M2-polarized TAMs presents a promising therapeutic strategy.
This study aims to identify a dual-function target in GC cells that drives both malignant phenotypes and M2 macrophage polarization, revealing its molecular mechanisms to provide novel therapeutic targets for selectivly targeting M2-polarized TAMs in GC.
Transcriptomic and clinical data from GC and adjacent tissues were utilized to identify mRNAs associated with high M2 macrophage infiltration and poor prognosis. Single-cell sequencing elucidated cell types expressing the target gene. Transwell co-culture and exosome intervention experiments demonstrated its role in M2 polarization. Small RNA sequencing of exosomes, western blotting, and CoIP assays revealed the molecular mechanisms underlying exosome-mediated M2 polarization. Protein array, ChIP and dual-luciferase reporter assays clarified the molecular mechanisms by which the target gene regulated exosomal miRNA. In vivo validation was performed using xenograft tumor models.
SERPINE1 was identified as a highly expressed mRNA in GC tissues and cells, significantly associated with advanced clinical stages, worse prognosis, and higher M2 macrophage infiltration in patients with GC. SERPINE1 overexpression in GC cells promoted tumor growth and M2 macrophage polarization. SERPINE1 facilitated the transfer of let-7 g-5p to macrophages via cancer-derived exosomes, inducing M2 polarization. Exosomal let-7 g-5p internalized by macrophages downregulated SOCS7 protein levels, disrupting its interaction with STAT3 and relieving the inhibition of STAT3 phosphorylation, thereby leading to STAT3 hyperactivation, which consequently drove M2 polarization. Additionally, in GC cells, elevated SERPINE1 expression activated JAK2, enhancing STAT3 binding to the let-7 g-5p promoter and promoting its transcription, thereby increasing let-7 g-5p levels in exosomes.
GC cell-derived SERPINE1, functioning as a primary driver of GC growth and TAM M2 polarization, promotes M2 polarization through the regulation of exosomal let-7 g-5p transfer via autocrine activation of the JAK2/STAT3 signaling pathway. These findings elucidate a novel mechanism of SERPINE1-induced M2 polarization and highlight SERPINE1 as a promising target for advancing immunotherapy and targeted treatments in GC.
肿瘤相关巨噬细胞（TAM），尤其是M2极化的TAM，是胃癌（GC）肿瘤进展、免疫逃逸和治疗抵抗的重要促成因素。尽管人们努力靶向TAM募集或耗竭，但临床疗效仍然有限。因此，鉴定特异性抑制或重编程M2极化TAM的靶点是一种有前景的治疗策略。
本研究旨在鉴定GC细胞中驱动恶性表型和M2巨噬细胞极化的双功能靶点，揭示其分子机制，为选择性靶向GC中M2极化TAM提供新的治疗靶点。
利用GC及癌旁组织的转录组和临床数据来鉴定与高M2巨噬细胞浸润和不良预后相关的mRNA。单细胞测序阐明了表达靶基因的细胞类型。Transwell共培养和外泌体干预实验证明了其在M2极化中的作用。外泌体的小RNA测序、蛋白质免疫印迹和免疫共沉淀实验揭示了外泌体介导的M2极化的分子机制。蛋白质芯片、染色质免疫沉淀和双荧光素酶报告基因实验阐明了靶基因调控外泌体miRNA的分子机制。使用异种移植肿瘤模型进行体内验证。
SERPINE1被鉴定为GC组织和细胞中高表达的mRNA，与GC患者的晚期临床分期、较差预后和较高的M2巨噬细胞浸润显著相关。GC细胞中SERPINE1的过表达促进肿瘤生长和M2巨噬细胞极化。SERPINE1通过癌症来源的外泌体促进let-7 g-5p向巨噬细胞的转移，诱导M2极化。巨噬细胞内化的外泌体let-7 g-5p下调SOCS7蛋白水平，破坏其与STAT3的相互作用，解除对STAT3磷酸化的抑制，从而导致STAT3过度激活，进而驱动M2极化。此外，在GC细胞中，SERPINE1表达升高激活JAK2，增强STAT3与let-7 g-5p启动子的结合并促进其转录，从而增加外泌体中let-7 g-5p的水平。
GC细胞来源的SERPINE1作为GC生长和TAM M2极化的主要驱动因子，通过JAK2/STAT3信号通路的自分泌激活调节外泌体let-7 g-5p转移，从而促进M2极化。这些发现阐明了SERPINE1诱导M2极化的新机制，并突出了SERPINE1作为推进GC免疫治疗和靶向治疗的有前景靶点。
