Zhao K, Xiao MM, Yang YS, Xiao X. Tumor microenvironment phenotyping guides precision therapy in unresectable pancreatic cancer. World J Gastrointest Oncol 2025; 17(10): 109830 [PMID: 41114111 DOI: 10.4251/wjgo.v17.i10.109830]
Corresponding Author of This Article
Xiao Xiao, MD, Research Fellow, Department of Endocrinology, Weifang People’s Hospital, No. 151 Guangwen Street, Kuiwen District, Weifang 261041, Shandong Province, China. xiaoxiao9011@sdsmu.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/
World J Gastrointest Oncol. Oct 15, 2025; 17(10): 109830 Published online Oct 15, 2025. doi: 10.4251/wjgo.v17.i10.109830
Tumor microenvironment phenotyping guides precision therapy in unresectable pancreatic cancer
Kai Zhao, Ming-Ming Xiao, Yong-Sheng Yang, Xiao Xiao
Kai Zhao, Yong-Sheng Yang, Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun 130041, Jilin Province, China
Ming-Ming Xiao, Department of Pancreatic Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China
Xiao Xiao, Department of Endocrinology, Weifang People’s Hospital, Weifang 261041, Shandong Province, China
Author contributions: Zhao K contributed to conceptualization, writing original draft, writing, review and editing; Xiao MM contributed to writing, review and editing, visualization; Yang YS contributed to writing, review and editing, supervision; Xiao X contributed to supervision, writing, review and editing, project administration; All authors read and approved the final manuscript.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
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: Xiao Xiao, MD, Research Fellow, Department of Endocrinology, Weifang People’s Hospital, No. 151 Guangwen Street, Kuiwen District, Weifang 261041, Shandong Province, China. xiaoxiao9011@sdsmu.edu.cn
Received: May 23, 2025 Revised: June 9, 2025 Accepted: September 8, 2025 Published online: October 15, 2025 Processing time: 144 Days and 18.5 Hours
Abstract
Treatment of locally advanced unresectable pancreatic cancer remains a major clinical challenge due to pronounced heterogeneity and resistance to standard regimens. Increasing evidence highlights the critical role of the tumor microenvironment (TME) in shaping therapeutic response and driving drug resistance. In this minireview, we summarize recent advances in TME phenotyping and its potential to guide precision therapy. A four-dimensional framework integrating stromal, immune, genomic, and metabolic features has been proposed to better characterize TME heterogeneity. Preclinical and clinical studies indicate that strategies targeting the stroma, modulating immunity, or exploiting genomic vulnerabilities such as homologous recombination deficiency may enhance the efficacy of chemotherapy, immunotherapy, and targeted agents. Dynamic biomarkers, including circulating tumor DNA and carbohydrate antigen 19-9, also show promise for real-time therapy adaptation, although their clinical application remains limited. By synthesizing current evidence, we emphasize the importance of individualized treatment strategies that account for TME complexity. While encouraging, the translation of multiomics phenotyping and biomarker monitoring into routine clinical practice requires standardization, prospective validation, and integration of novel technologies. Future research should focus on establishing reproducible TME-guided models to enable dynamic and personalized therapy for patients with unresectable pancreatic cancer.
Core Tip: This review highlights the importance of tumor microenvironment (TME) heterogeneity in treatment resistance for unresectable locally advanced pancreatic cancer. We propose a novel four-dimensional TME phenotyping framework integrating fibrosis, immunity, genomics, and metabolism to guide precision therapy. This approach enables dynamic, individualized treatment strategies and offers new prospects for improving patient outcomes.
