ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1689468
This article is part of the Research TopicTargeting cancer-associated fibroblasts: Disrupting immune evasion and therapy resistanceView all 9 articles
APE1 Mediates Chemoresistance in Esophageal Squamous Cell Carcinoma by Remodeling the Immunosuppressive Microenvironment
Provisionally accepted
Gao Han1
Rao Junji1Xiao He2Kuang Xunjie2Wang Yong2Yao Yujing2Yang Yuxin2Li Mengxia2Liao Xiuyong1*Wang Dong1*- 1Chongqing Qianjiang Central Hospital, Qianjiang, China
- 2Army Medical Center of PLA, Chongqing, China
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Background: Squamous cell carcinoma of the esophagus (ESCC) has poor prognosis after surgery and adjuvant chemotherapy. Biomarkers predicting treatment efficacy are urgently needed. This study investigated apurinic/apyrimidinic endonuclease 1 (APE1), a key DNA repair enzyme, as a prognostic biomarker in ESCC patients receiving postoperative chemotherapy. Objective: To assess the relationship between APE1 expression and survival outcomes post-adjuvant chemotherapy. Method: 115 ESCC patients receiving surgery and platinum-based chemotherapy were retrospectively enrolled. APE1 expression (low, medium, high) was determined by immunohistochemistry (IHC). Furthermore, external validation was performed using a tissue microarray cohort of 110 post-chemotherapy ESCC patients and the GES5325 dataset. Survival was analyzed using Kaplan-Meier and Cox regression. The tumor immune microenvironment (TIME) was characterized by multiplex immunofluorescence (mIF). Results: High APE1 expression correlated significantly with advanced T stage (p=0.005) and neural invasion (p=0.036). The high-expression group had significantly worse 5-year OS (27% vs. 91.4%) and DFS (14.3% vs. 55.3%) than the low-expression group (p<0.001), confirmed in public databases. Multivariate analysis identified APE1 expression (DFS: HR=4.600, 95% CI 1.285-16.466; OS: HR=16.001, 95% CI 4.826-53.061) and clinical stage as independent prognostic factors. Additionally, external validation was carried out using tissue microarrays and the GEO database to confirm the reliability. mIF analysis revealed significantly increased infiltration of FOXP3+ regulatory T cells (Treg) and cancer-associated fibroblasts (CAFs) in the APE1-high group. Conclusion: High APE1 expression is an independent predictor of poor prognosis in ESCC patients receiving postoperative chemotherapy, associated with Treg and CAFs-mediated immunosuppression. APE1 serves as a prognostic biomarker linked to immunosuppression, enabling personalized adjuvant therapy.
Keywords: Ape1, esophageal squamous cell carcinoma, chemotherapy, survival analysis, CAF
Received: 20 Aug 2025; Accepted: 14 Oct 2025.
Copyright: © 2025 Han, Junji, He, Xunjie, Yong, Yujing, Yuxin, Mengxia, Xiuyong and Dong. 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:
Liao Xiuyong, xiuyongliaotumor@cqu.edu.cn
Wang Dong, wangdong64@cqu.edu.cn
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