FSCN1/ACK1 axis-dependent M2 macrophage polarization fuels colorectal cancer progression

doi:10.3748/wjg.121025

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Basic Study

Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastroenterol. Nov 28, 2026; 32(44): 121025
Published online Nov 28, 2026. doi: 10.3748/wjg.121025

FSCN1/ACK1 axis-dependent M2 macrophage polarization fuels colorectal cancer progression

Zhu Wang, Chao Liu, Hao Liu, Yong Jiang, Yan Ma

Zhu Wang, Hao Liu, Yong Jiang, Yan Ma, Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China

Chao Liu, Department of Laser Cosmetic Clinic, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China

Co-first authors: Zhu Wang and Chao Liu.

Author contributions: Wang Z and Liu C have made equal contributions, including study design, data collection and analysis, and manuscript preparation as co-first authors; Liu H and Jiang Y designed the experiments and conducted clinical data collection, performed postoperative follow-up and recorded the data; Wang Z, Liu C and Ma Y conducted the collation and statistical analysis, and wrote the original manuscript and revised the paper; all authors read and approved the final manuscript.

AI contribution statement: No AI tools were used in writing, editing, or generating any part of this manuscript, including text, images, and data analysis.

Institutional review board statement: The study was approved by the Institutional Review Board of Shandong Provincial Hospital Affiliated to Shandong First Medical University.

Institutional animal care and use committee statement: The study was approved by the Animal Ethics Committee of Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. HSRF2025-072.

Conflict-of-interest statement: All authors declare no conflict of interest in publishing the manuscript.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Data sharing statement: All data generated or analyzed during this study are included in this published article.

Corresponding author: Yan Ma, Associate Chief Physician, Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324 Jingwu Weiqi Road, Huaiyin District, Jinan 250021, Shandong Province, China. lilepingsph@163.com

Received: May 12, 2026
Revised: June 11, 2026
Accepted: July 29, 2026
Published online: November 28, 2026
Processing time: 140 Days and 17.5 Hours

Abstract

BACKGROUND

Fascin actin-bundling protein-1 (FSCN1) is upregulated in colorectal cancer (CRC) and correlated with poor prognosis. However, its role in shaping the tumor-immune microenvironment remains poorly understood.

AIM

To elucidate the mechanism by which FSCN1 regulates macrophage polarization and promotes CRC progression.

METHODS

FSCN1 expression was assessed in human CRC tissues and cell lines. Functional assays evaluated the effects of FSCN1 knockdown on CRC cell proliferation, migration, and invasion in vitro and on tumor growth in a nude mouse xenograft model in vivo. Macrophage polarization was analyzed using conditioned medium from FSCN1-manipulated CRC cells. Mechanistic studies employed rescue experiments with ACK1 overexpression to validate the FSCN1/ACK1 signaling axis.

RESULTS

FSCN1 was significantly upregulated in CRC tissues and positively correlated with M2-type tumor-associated macrophage infiltration. FSCN1 knockdown suppressed CRC cell malignant behavior in vitro and inhibited tumor growth in vivo. Mechanistically, FSCN1 silencing reduced activated Cdc42-associated kinase 1 (ACK1) expression. Conditioned medium from FSCN1-deficient CRC cells reprogrammed macrophages toward an M1-like phenotype, as evidenced by increased CD80, inducible nitric oxide synthase, and interleukin-12 and decreased CD206, arginase 1, and interleukin-10. Crucially, ACK1 overexpression reversed this M1 repolarization, confirming that FSCN1 drives M2 polarization via ACK1. In vivo, FSCN1 knockdown delayed tumor onset, reduced Ki67-positive cells, and reshaped the microenvironment toward a less immunosuppressive state.

CONCLUSION

The FSCN1/ACK1 axis promotes CRC progression by facilitating M2 macrophage polarization, highlighting it as a potential therapeutic target for restoring antitumor immunity in CRC.

Keywords: Colon cancer; Fascin actin-bundling protein-1; Activated Cdc42-associated kinase 1; Macrophage; M2 polarization

Core Tip: This study reveals that fascin actin-bundling protein-1 (FSCN1) promotes colorectal cancer progression by driving M2 macrophage polarization via activated Cdc42-associated kinase 1. FSCN1 knockdown reprograms macrophages toward an anti-tumor M1 phenotype and suppresses tumor growth, identifying the FSCN1/activated Cdc42-associated kinase 1 axis as a therapeutic target for restoring anti-tumor immunity.