©Author(s) (or their employer(s)) 2026. No commercial re-use. See Permissions. Published by Baishideng Publishing Group Inc.
Distribution and prognostic value of macrophages in colorectal cancer and adjacent mucosa in patient stages I-III vs IV
Wen-Jing Ye, Esraa Ali, Sergii Pavlov, Lenka Červenková, Filip Ambrozkiewicz, Ondřej Vyčítal, Petr Hošek, František Zitrický, Ondřej Daum, Václav Liška, Kari Hemminki, Andriy Trailin
Wen-Jing Ye, Esraa Ali, Sergii Pavlov, Filip Ambrozkiewicz, František Zitrický, Andriy Trailin, Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen 32300, Czech Republic
Lenka Červenková, Ondřej Vyčítal, Petr Hošek, Ondřej Daum, Václav Liška, Laboratory of Cancer Treatment and Tissue Regeneration, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen 32300, Czech Republic
Ondřej Vyčítal, Václav Liška, Department of Surgery, University Hospital and Faculty of Medicine in Pilsen, Charles University, Pilsen 32300, Czech Republic
Ondřej Daum, Department of Pathology, Regional Hospital Liberec, Liberec 46001, Czech Republic
Kari Hemminki, Department of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg 69120, Germany
Kari Hemminki, Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Pilsen 32300, Czech Republic
Co-first authors: Wen-Jing Ye and Esraa Ali.
Author contributions: Ye WJ and Ali E were responsible for data curation, writing original draft, and formal analysis as co-first authors; Pavlov S, Červenková L, Ambrozkiewicz F, Vyčítal O, Daum O, and Trailin A were responsible for data curation and methodology; Pavlov S, Červenková L, Ambrozkiewicz F, Vyčítal O, and Trailin A were responsible for formal analysis; Liška V and Hemminki K were responsible for resources, funding acquisition, and project administration; Liška V, Hemminki K, and Trailin A were responsible for validation, review and editing; Hemminki K and Trailin A were responsible for conceptualization and supervision; all authors have read and agreed to the published version of the manuscript.
Supported by Ministry of Health of Czech Republic, No. NU21-03-00506; and Czech National Institute for Cancer Research, No. LX22NPO5102.
Institutional review board statement: The study was approved by the Ethics Committee of the Faculty of Medicine and University Hospital in Pilsen.
Informed consent statement: The need for informed consent was waived by the Ethics Committee of the Faculty of Medicine and University Hospital in Pilsen.
Conflict-of-interest statement: All authors declare no conflict of interest in publishing the manuscript.
STROBE statement: The authors have read the STROBE Statement – checklist of items, and the manuscript was prepared and revised according to the STROBE Statement – checklist of items.
Data sharing statement: All data generated or analyzed during this study are included in this article and its additional material files. Further enquiries can be directed to the corresponding author.
Corresponding author: Andriy Trailin, MD, PhD, Senior Researcher, Laboratory of Translational Cancer Genomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1665/76, Pilsen 32300, Czech Republic.
andriy.trailin@lfp.cuni.cz
Received: October 13, 2025
Revised: November 20, 2025
Accepted: January 8, 2026
Published online: March 14, 2026
Processing time: 145 Days and 3.1 Hours
BACKGROUND
Synchronous and metachronous liver metastases (LM) of colorectal cancer (CRC) drastically worsen the patient’s survival. The biological and immunological mechanisms underlying these distinct metastatic trajectories remain incompletely understood. Prognostic impact of macrophages in primary CRC (pCRC) is uncertain, with discrepant findings reported for different macrophage subsets and different stage of the disease. Most of prior studies of tumor-infiltrating macrophages in CRC have focused primarily on the tumor core or invasive margin, whereas less attention has been given to the adjacent nontumor mucosa (NM), which may harbor early immunological alterations that precede or accompany metastatic spread.
AIM
To evaluate distribution and prognostic value of macrophages in pCRC and NM in patients at stage I-III vs IV.
METHODS
Paired specimens of pCRC and NM were collected retrospectively from: (1) Stage IV (n = 55) patients with synchronous LM; and (2) Stage I-III (n = 44) patients who developed metachronous LM thereafter. After immunohistochemical staining CD68+ (M0), CD80+ (M1), CD206+ and CD163+ (M2) macrophages were quantified in NM and tumor center (TC) of pCRC. Cell densities in NM and TC and TC/NM ratios were tested as prognostic variables for overall survival since liver surgery. Cox-regression and Kaplan-Meier analyses were applied using the R environment.
RESULTS
Densities of macrophages followed the declining pattern from CD163+ through CD206+ and CD68+ to CD80+ in both NM and TC, with significantly smaller densities of all cell types in tumors. Greater densities of CD80+ cells were observed in NM in stage I-III over stage IV patients: 309 (24-1143) cells/mm2vs 208 (3-1084) cells/mm2 [median (minimum-maximum), P = 0.04]. High CD163+ cell density in NM in stage IV [hazard ratio = 0.45 (95%CI: 0.22-0.95), P = 0.04] and CD80+ cell density in NM in stage I-III [hazard ratio = 0.24 (95%CI: 0.10-0.57), P = 0.001] were associated with longer overall survival.
CONCLUSION
Contrary to TC of pCRC, we found favorable prognostic implications of macrophages in NM, driven by distinct subsets of macrophages in stage IV (CD163+ M2) and stage I-III CRC (CD80+ M1).
Core Tip: Limited evidence exists regarding the distribution and prognostic associations of different subsets of macrophages in colorectal cancer (CRC) and adjacent nontumor mucosa (NM) in patients stage IV with synchronous liver metastases or stage I-III who developed metachronous liver metastases thereafter. This retrospective cohort study included 55 stage IV and 44 stage I-III patients. M2-macrophages outnumbered M1 and M0 both in primary CRC and NM with significantly reduced cell densities in tumor tissue. Greater density of M1 macrophages is a hallmark of NM in stage I-III CRC. Higher densities of macrophages in NM demonstrate favorable associations with survival.
