The VASN-YAP-MYL9 axis drives M2-like macrophage polarization and immune evasion in colorectal cancer.
5 affiliations
- 1Department of Radiology and Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, Guangdong, 510655, China.
- 2The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Naval Medical University, Shanghai, 200438, China.
- 3Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510655, China.
- 4Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, 510655, China. [email protected].
- 5Department of Radiology and Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Erheng Road, Guangzhou, Guangdong, 510655, China. [email protected].
Abstract
Background
Tumor-associated macrophages (TAMs) polarized toward an M2-like phenotype are critical drivers of immunosuppression in colorectal cancer (CRC). While Vasorin (VASN) is implicated in poor prognosis, its specific role in orchestrating the tumor immune microenvironment remains elusive.Methods
VASN expression and immune infiltration were analyzed using TCGA transcriptomics and single-cell transcriptomics, validated via immunohistochemistry and immunofluorescence in CRC patient cohorts. In vitro Transwell co-cultures and ELISA were utilized to assess cytokine secretion. In vivo VASN functions were evaluated using syngeneic mouse models alongside clodronate liposome-mediated macrophage depletion. Molecular interactions were delineated utilizing chromatin immunoprecipitation (ChIP), dual-luciferase reporter assays, and genetic rescue strategies.Results
VASN was significantly upregulated in CRC tissues and correlated with M2-like macrophage abundance and reduced survival. In vivo, VASN promoted tumor growth and suppressed CD8⁺ T cell effector function; crucially, these effects were significantly attenuated by macrophage depletion. Mechanistically, VASN activated the Hippo-YAP pathway, facilitating the YAP/TEAD4 complex to directly activate MYL9 transcription. This VASN-YAP-MYL9 axis triggered the paracrine secretion of IL-4 and IL-13 from tumor cells, driving neighboring macrophages toward an M2-like phenotype. This polarization subsequently impaired cytotoxic surveillance, facilitating immune evasion.Conclusion
This study identifies a novel VASN-YAP-MYL9 axis that reprograms macrophages to mediate immune escape. These findings broaden our understanding of CRC immune evasion and provide a rational framework for targeting VASN to remodel the immunosuppressive microenvironment and augment therapeutic efficacy.
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BibTeX
@article{liang2026vasnyapmyl9,
title = {{The VASN-YAP-MYL9 axis drives M2-like macrophage polarization and immune evasion in colorectal cancer.}},
author = {Weiye Liang and Gengjia Chen and Huancheng Yang and Mingkai Liu and Yandong Zhao and Yuling Su and Xiaochun Meng},
journal = {Journal of translational medicine},
year = {2026},
month = aug,
doi = {10.1186/s12967-026-08741-7},
url = {https://europepmc.org/article/MED/42958563},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - The VASN-YAP-MYL9 axis drives M2-like macrophage polarization and immune evasion in colorectal cancer.
AU - Weiye Liang
AU - Gengjia Chen
AU - Huancheng Yang
AU - Mingkai Liu
AU - Yandong Zhao
AU - Yuling Su
AU - Xiaochun Meng
PY - 2026
DA - 2026/08/03
JO - Journal of translational medicine
DO - 10.1186/s12967-026-08741-7
UR - https://europepmc.org/article/MED/42958563
AB - Background Tumor-associated macrophages (TAMs) polarized toward an M2-like phenotype are critical drivers of immunosuppression in colorectal cancer (CRC). While Vasorin (VASN) is implicated in poor prognosis, its specific role in orchestrating the tumor immune microenvironment remains elusive.Methods VASN expression and immune infiltration were analyzed using TCGA transcriptomics and single-cell transcriptomics, validated via immunohistochemistry and immunofluorescence in CRC patient cohorts. In vitro Transwell co-cultures and ELISA were utilized to assess cytokine secretion. In vivo VASN functions were evaluated using syngeneic mouse models alongside clodronate liposome-mediated macrophage depletion. Molecular interactions were delineated utilizing chromatin immunoprecipitation (ChIP), dual-luciferase reporter assays, and genetic rescue strategies.Results VASN was significantly upregulated in CRC tissues and correlated with M2-like macrophage abundance and reduced survival. In vivo, VASN promoted tumor growth and suppressed CD8⁺ T cell effector function; crucially, these effects were significantly attenuated by macrophage depletion. Mechanistically, VASN activated the Hippo-YAP pathway, facilitating the YAP/TEAD4 complex to directly activate MYL9 transcription. This VASN-YAP-MYL9 axis triggered the paracrine secretion of IL-4 and IL-13 from tumor cells, driving neighboring macrophages toward an M2-like phenotype. This polarization subsequently impaired cytotoxic surveillance, facilitating immune evasion.Conclusion This study identifies a novel VASN-YAP-MYL9 axis that reprograms macrophages to mediate immune escape. These findings broaden our understanding of CRC immune evasion and provide a rational framework for targeting VASN to remodel the immunosuppressive microenvironment and augment therapeutic efficacy.
SN - 1479-5876
ER -