Zhang XM, Zhao FY, Gao LF, Xu T, Yang F, Qian NS. Immune therapy-related hyperprogressive disease: Molecular mechanisms, biomarkers, and clinical strategies. World J Clin Oncol 2025; 16(12): 110351 [DOI: 10.5306/wjco.v16.i12.110351]
Corresponding Author of This Article
Nian-Song Qian, MD, Chief Physician, Department of Thoracic Oncology, Respiratory and Critical Care Medicine, The Eighth Medical Center of People’s Liberation Army General Hospital, No. A17 Heishanhu Road, Haidian District, Beijing 100091, China. qianniansong1@163.com
Research Domain of This Article
Oncology
Article-Type of This Article
Minireviews
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/
World J Clin Oncol. Dec 24, 2025; 16(12): 110351 Published online Dec 24, 2025. doi: 10.5306/wjco.v16.i12.110351
Immune therapy-related hyperprogressive disease: Molecular mechanisms, biomarkers, and clinical strategies
Xiao-Ming Zhang, Fei-Yu Zhao, Lin-Feng Gao, Tao Xu, Fan Yang, Nian-Song Qian
Xiao-Ming Zhang, Tao Xu, Nian-Song Qian, Department of Thoracic Oncology, Respiratory and Critical Care Medicine, The Eighth Medical Center of People’s Liberation Army General Hospital, Beijing 100091, China
Xiao-Ming Zhang, Lin-Feng Gao, Department of Oncology, The 93263 Unit of The Chinese PLA, Jinzhou 100039, Liaoning Province, China
Fei-Yu Zhao, Department of Radiation Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China
Fan Yang, Department of Oncology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China
Co-first authors: Xiao-Ming Zhang and Fei-Yu Zhao.
Author contributions: Zhang XM and Zhao FY wrote the article, they contributed equally to this article, they are the co-first authors of this manuscript; Gao LF and Xu T revised the article, Yang F reviewed the article, Qian NS provided writing ideas; and all authors thoroughly reviewed and endorsed the final manuscript.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest 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: Nian-Song Qian, MD, Chief Physician, Department of Thoracic Oncology, Respiratory and Critical Care Medicine, The Eighth Medical Center of People’s Liberation Army General Hospital, No. A17 Heishanhu Road, Haidian District, Beijing 100091, China. qianniansong1@163.com
Received: June 5, 2025 Revised: July 5, 2025 Accepted: November 11, 2025 Published online: December 24, 2025 Processing time: 201 Days and 20.7 Hours
Abstract
Programmed death receptor-1 inhibitors have significantly improved the prognosis of various malignancies. Nevertheless, hyperprogressive disease (HPD), recognized as a severe adverse reaction to immunotherapy, causes a substantial surge in tumor burden and notably shortens the survival of 4%-29% of patients. This article comprehensively reviews the controversies regarding the clinical definition of HPD, its cross-cancer epidemiological features (encompassing gastric cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, etc.), and potential molecular mechanisms (such as MDM2/MDM4 gene amplification, EGFR mutations, and reprogramming of the immune microenvironment). It further delves into biomarker-based predictive models, targeted combination therapy strategies, and salvage treatment alternatives. Ultimately, it puts forward future directions, including the establishment of a multicenter HPD registry database and organoid predictive models, aiming to offer evidence-based guidance for clinical practice.
Core Tip: Immune checkpoint inhibitor-induced hyperprogressive disease represents a paradoxical clinical phenomenon characterized by accelerated tumor progression mediated through complex immunosuppressive mechanisms involving regulatory T cells expansion, M2-type tumor-associated macrophages polarization, and myeloid-derived suppressor cells accumulation within the tumor microenvironment, coupled with oncogenic alterations such as MDM2 amplification and EGFR activation. Current predictive approaches integrate liquid biopsy profiling (e.g., circulating tumor DNA and blood tumor mutational burden dynamics) with systemic inflammatory markers (e.g., neutrophil-to-lymphocyte ratio and lactate dehydrogenase ratios), while emerging therapeutic strategies focus on combinatorial approaches targeting immunosuppressive networks, metabolic reprogramming, and checkpoint inhibition. This multifaceted pathogenesis underscores the critical need for mechanistic elucidation and translational development of precision management algorithms to mitigate this life-threatening complication of cancer immunotherapy.
