Wang Z, Zhang RY, Xu YF, Yue BT, Zhang JY, Wang F. Unmasking immune checkpoint resistance in esophageal squamous cell carcinoma: Insights into the tumor microenvironment and biomarker landscape. World J Gastrointest Oncol 2025; 17(8): 109489 [DOI: 10.4251/wjgo.v17.i8.109489]
Corresponding Author of This Article
Feng Wang, MD, PhD, Professor, Senior Researcher, Senior Scientist, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No. 50 Eastern Jianshe Road, Zhengzhou 450052, Henan Province, China. zzuwangfeng@zzu.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Review
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Zhe Wang, Rui-Ying Zhang, Feng Wang, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
Yi-Fan Xu, Bing-Tong Yue, Jia-Yi Zhang, Department of Clinical Medicine, The First Clinical Medical College of Zhengzhou University, Zhengzhou 45000, Henan Province, China
Co-first authors: Zhe Wang and Rui-Ying Zhang.
Co-corresponding authors: Jia-Yi Zhang and Feng Wang.
Author contributions: Wang Z and Zhang RY contributed equally to this work as co-first authors; Zhang JY and Wang F contributed equally to this work as co-corresponding authors; Wang Z drafted the original manuscript; Zhang RY, Xu YF and Yue BT carried out the literature search and helped structure the review; Zhang JY and Wang F conceived and supervised the study and made critical revisions; all authors prepared the draft and approved the submitted version.
Conflict-of-interest statement: The authors declare no conflict of interests for this article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Feng Wang, MD, PhD, Professor, Senior Researcher, Senior Scientist, Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No. 50 Eastern Jianshe Road, Zhengzhou 450052, Henan Province, China. zzuwangfeng@zzu.edu.cn
Received: May 13, 2025 Revised: June 2, 2025 Accepted: July 16, 2025 Published online: August 15, 2025 Processing time: 93 Days and 15 Hours
Abstract
Esophageal squamous cell carcinoma (ESCC) remains a daunting global health concern. It is marked by aggressive progression and poor survival. While immunotherapy has emerged as a promising treatment modality, both primary and acquired resistance continue to limit its clinical impact, leaving many patients without durable benefits (e.g., CheckMate-648, ESCORT-1st). This review explains resistance mechanisms and suggests new strategies to improve outcomes. These mechanisms include immunosuppressive cells (Treg cells, myeloid-derived suppressor cells), inhibitory cytokines, molecular alterations involving programmed death 1/programmed death-ligand 1 signaling, and impaired antigen presentation. We also highlight key clinical trials—for example, CheckMate-648 and ESCORT-1st—that reveal both the potential and pitfalls of current immune checkpoint blockade strategies, underscoring the need for robust predictive biomarkers. Moreover, we examine cutting-edge tactics to overcome resistance, including combination regimens, tumor microenvironment remodeling, and tailored treatment approaches rooted in the patient’s unique genomic and immunologic landscape.
Core Tip: Esophageal squamous cell carcinoma (ESCC) poses significant clinical challenges due to its aggressive progression and poor survival outcomes. While immunotherapy offers promise, resistance—both primary and acquired—remains a major hurdle, limiting its efficacy. This review explores the mechanisms of immunotherapy resistance in ESCC, including immunosuppressive cells, inhibitory cytokines, and molecular alterations in programmed death 1/programmed death-ligand 1 signaling. We also examine emerging strategies to overcome resistance, such as combination therapies and tumor microenvironment remodeling, emphasizing the need for predictive biomarkers to improve patient outcomes.
