The VASN-YAP-MYL9 axis drives M2-like macrophage polarization and immune evasion in colorectal cancer

Abstract

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. 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. 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. 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.