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Microbiota-driven immunometabolic regulation in colorectal cancer: Mechanisms and therapeutic opportunities
Wen-Yu Luan, Shu-Ping Zhang, Kai-Zhen Xu, Yu-Hui Shang, Wen-Jian Hu, Hui Sun, Yan-Dong Miao
Wen-Yu Luan, Shu-Ping Zhang, Kai-Zhen Xu, Yu-Hui Shang, Wen-Jian Hu, Yan-Dong Miao, Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2nd Medical College of Binzhou Medical University, Yantai 264100, Shandong Province, China
Wen-Yu Luan, Yu-Hui Shang, Hui Sun, Yan-Dong Miao, Research and Translational Center for Immunological Disorders, Binzhou Medical University, Yantai 264100, Shandong Province, China
Kai-Zhen Xu, Department of Comprehensive Oncology V, Shandong Provincial Public Health Clinical Centre, Jinan 250000, Shandong Province, China
Yan-Dong Miao, Guangdong Provincial Key Laboratory of Medical Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510000, Guangdong Province, China
Yan-Dong Miao, Department of Oncology, Xinhui District People's Hospital, Jiangmen 529100, Guangdong Province, China
Co-first authors: Wen-Yu Luan and Shu-Ping Zhang.
Co-corresponding authors: Hui Sun and Yan-Dong Miao.
Author contributions: Luan WY and Zhang SP contribute equally to this study as co-first authors; Luan WY performed the literature retrieval, wrote the manuscript, and images drawing; Zhang SP, Xu KZ, Shang YH, and Hu WJ performed the data analysis; Sun H and Miao YD were designated as co-corresponding authors. Sun H was responsible for the evolution of overarching research goals and aims, specifically critical review, management and coordination responsibility for the research activity planning and execution, acquisition of the financial support for the project leading to this publication, while Miao YD was responsible for review and editing the draft, oversight, and leadership responsibility for the research activity planning and execution, including mentorship external to the core team; all authors approved the final manuscript.
Supported by Shandong Province Medical and Health Science and Technology Development Plan Project, No. 202203030713; Yantai Science and Technology Program, No. 2024YD005, No. 2024YD007, and No. 2024YD010; and Science and Technology Program of Yantai Affiliated Hospital of Binzhou Medical University, No. YTFY2022KYQD06.
Conflict-of-interest statement: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Corresponding author: Yan-Dong Miao, MD, Cancer Center, Yantai Affiliated Hospital of Binzhou Medical University, The 2
nd Medical College of Binzhou Medical University, No. 717 Jinbu Street, Muping District, Yantai 264100, Shandong Province, China.
miaoyd_22@bzmc.edu.cn
Received: October 24, 2025
Revised: December 9, 2025
Accepted: December 30, 2025
Published online: March 15, 2026
Processing time: 140 Days and 9.7 Hours
Colorectal cancer (CRC) is a highly prevalent and lethal malignancy worldwide, marked by a multifaceted pathogenesis that involves various genetic, environmental, and lifestyle factors. Recent studies have increasingly underscored the significant role of gut microbiota in CRC, particularly focusing on how these microorganisms can modulate the host’s immune and metabolic processes. Metabolites produced by gut microbiota function as crucial signaling molecules that can have profound impacts on immune cell activity, contributing to the remodeling of the tumor microenvironment (TME). This, in turn, can influence critical aspects of cancer biology, including tumor initiation, progression, and the efficacy of therapeutic interventions. This review delves into the complex interactions that exist between gut microbiota and immunometabolism within the context of CRC, paying particular attention to how microbiota-mediated regulation of immunometabolism can affect the TME. Additionally, we explore the potential applications of these insights in enhancing the effectiveness of radiotherapy for CRC treatment. By synthesizing the latest findings from both clinical and preclinical studies, we aim to highlight the prospects of targeting gut microbiota as a novel therapeutic strategy, thereby offering a theoretical framework and fresh perspectives for precision treatment approaches in CRC management.
Core Tip: The treatment of colorectal cancer (CRC) faces challenges of drug resistance mediated by the tumor microenvironment (TME). This review proposes that the gut microbiota is a core regulator in reshaping CRC immune metabolism and TME. We have established an integrated framework of the “microbiota-immune metabolism-TME” axis, systematically elaborating on the mechanisms of CRC occurrence, development, and treatment resistance from the micro level to the macro level. This perspective provides new ideas for deconstructing complexities such as clinical drug resistance. Based on this, we further explore translational strategies targeting the microbiota to reverse immunosuppression, enhance the efficacy of radiotherapy, chemotherapy, and immunotherapy, offering innovative theoretical basis and intervention prospects for the precise treatment of CRC.
