Xu JJ, Ni CX, Wang P, Qin LD, Xu JJ. Advancing human epidermal growth factor receptor 2-positive gastric cancer therapy: Toward targeted immunotherapy and antibody-drug conjugates. World J Gastrointest Oncol 2026; 18(5): 116882 [DOI: 10.4251/wjgo.v18.i5.116882]
Corresponding Author of This Article
Jia-Ju Xu, MD, Department of Medical Oncology, Tai’an City Central Hospital, No. 29 Longtan Road, Tai’an 271000, Shandong Province, China. jiajuxu1101@163.com
Research Domain of This Article
Oncology
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/
Jia-Ju Xu, Department of Pediatrics, Yantai Yuhuangding Hospital, Yantai 264000, Shandong Province, China
Chun-Xiao Ni, Department of Minimally Invasive Oncology, Tai’an City Central Hospital, Tai’an 271000, Shandong Province, China
Ping Wang, Li-Dong Qin, Jia-Ju Xu, Department of Medical Oncology, Tai’an City Central Hospital, Tai’an 271000, Shandong Province, China
Co-first authors: Jia-Ju Xu and Chun-Xiao Ni.
Author contributions: Xu JJ and Ni CX are co-first authors, the two authors made equal contributions to this work and played essential roles in the critical stages of research design, data collection and analysis, and manuscript preparation; Xu JJ drafted the initial manuscript; Ni CX collected, analyzed the data, and contributed to the discussion of results; Wang P and Qin LD assisted in data collection and analysis; Xu JJ (corresponding author) conceived and designed the review and critically revised the manuscript for important intellectual content.
AI contribution statement: No portion of the main text was AI-generated; however, we used an AI-assisted language polishing tool (Grammarly) for minor grammatical and stylistic improvements. AI tools were only used for language polishing and spelling/grammar checking, not for data analysis, interpretation, or study design.
Supported by the Scientific Research Fund of Tai’an Science and Technology Agency, No. 2019NS180.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Corresponding author: Jia-Ju Xu, MD, Department of Medical Oncology, Tai’an City Central Hospital, No. 29 Longtan Road, Tai’an 271000, Shandong Province, China. jiajuxu1101@163.com
Received: November 24, 2025 Revised: January 15, 2026 Accepted: February 10, 2026 Published online: May 15, 2026 Processing time: 172 Days and 7.2 Hours
Abstract
The prevalence of human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) reflects a distinct subtype of this malignancy, characterized by unique molecular properties and clinical behavior. Revolutionary developments in the therapeutic arena of HER2-positive GC have included advances in targeted therapy, immunotherapy, and antibody-drug conjugates. This review summarizes the knowledge on the molecular basis and current therapeutic advances in HER2-positive GC, with particular focus on the recent advances in overcoming drug resistance and improving therapeutic efficacy such as antibody-drug conjugate therapies (including trastuzumab deruxtecan and disitamab vedotin) and combined modality therapies that combine targeted therapy, immunotherapy, and chemotherapy (e.g., the KEYNOTE-811 regimen) which demonstrate breakthroughs in overcoming drug resistance. The article also focuses on a detailed discussion of the complex mechanisms of resistance associated with HER2 variants, bypass signaling activation and tumor heterogeneity and suggests the corresponding countermeasures, in terms of dual HER2 blockade, and cyclin-dependent kinase 4/6 inhibitor combinations. Lastly, this review states the future directions in precision medicine framework involving liquid biopsy, multi-omics analysis, and artificial intelligence, to provide comprehensive perspectives and future guidance in advancing the personalized treatment models and clinical decision-making in HER2-positive GC.
Core Tip: The therapeutic profile of human epidermal growth factor receptor 2 (HER2)-positive gastric cancer is shifting to a paradigm where it is no longer dependent on the traditional HER2 inhibition. This change has been achieved by two important developments: Potent antibody-drug conjugates and combined modality therapies targeting HER2, immune checkpoints, and chemotherapy. Our review provides a critical analysis of these approaches, deconstructs the multifaceted molecular basis of resistance, and conceptualizes a next-generation precision oncology framework combining real-time monitoring with liquid biopsy and analytics driven by artificial intelligence to outsmart gastric cancer evolution.
