ORIGINAL RESEARCH article
Front. Med.
Sec. Gene and Cell Therapy
Volume 12 - 2025 | doi: 10.3389/fmed.2025.1636699
This article is part of the Research TopicInnovations and Challenges in Gene and Cell Therapy: From Bench to BedsideView all 3 articles
Malignant epithelia cells-derived spermine induces APOE+ macrophages to suppress tumor immunity in adenocarcinoma of the esophagogastric junction
Provisionally accepted
Yan Zhang1,2
Zhaoyang Liu1Huihui Sun1,2
Zhenxiang Wang1,2Ye Chen1,2Zhiqian Hu1,2
XINxing Li2
Kai Xu1,2Ying Chen1,2Yanping Xu1*
Chenfei Wang1*
Shuchang Xu1,2*- 1Tongji University, Shanghai, China
- 2Tongji Hospital Affiliated to Tongji University, Shanghai, China
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Adenocarcinoma of the esophagogastric junction (AEG) is increasingly recognized as a distinct gastrointestinal tumor type with a poor prognosis. However, the mechanisms driving AEG progression, particularly the interplay between metabolic reprogramming and the immune microenvironment, remain poorly understood. We integrated multi-omics to profile the tumor microenvironment and metabolic reprogramming of AEG. Tumor tissues and paired normal adjacent tissues from AEG patients were subjected to single-cell RNA sequencing (N=11), spatial transcriptomics (N=4), and metabolomics analysis (N=26). Molecular experiments and animal models were used for validation.Our analysis revealed an AEG-specific malignant subtype originating from the esophagogastric junction, characterized by heightened proliferation and poor differentiation. These malignant cells exhibited metabolic reprogramming marked by hyperactivation of the glutamine-arginine-spermine axis with concomitant spermine accumulation. Spermine was found to drive the polarization of tumor-associated macrophages into an APOE + immunosuppressive phenotype, thereby modulating the tumor immune microenvironment. Mechanistically, spermine promoted the phosphorylation of STAT3, thereby enhancing its binding affinity to the APOE promoter region and leading to enhanced transcriptional activation of APOE.This study identified AEG-like malignant cells as a high-risk subtype, revealed the metabolic-immune crosstalk driven by the spermine-STAT3-APOE axis in AEG progression, and provided potential targets for AEG metabolic intervention and immunotherapy.
Keywords: Adenocarcinoma of the esophagogastric junction, single-cell RNA sequencing, Spatial transcriptomics, Cancer Metabolism, Tumor Microenvironment
Received: 25 Jun 2025; Accepted: 29 Jul 2025.
Copyright: © 2025 Zhang, Liu, Sun, Wang, Chen, Hu, Li, Xu, Chen, Xu, Wang and Xu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Yanping Xu, Tongji University, Shanghai, China
Chenfei Wang, Tongji University, Shanghai, China
Shuchang Xu, Tongji University, Shanghai, China
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