FLNA Expression in Cancer-Associated Fibroblasts Is Associated with Immunosuppression and Tumor Progression in Colorectal Cancer

Abstract

Background The role of Filamin A (FLNA) in colorectal cancer (CRC), particularly within the stromal compartment, remains poorly defined. This study investigates its expression, function, and clinical relevance in CRC. Methods We integrated transcriptomic data from the GSE39582 training cohort and TCGA/GSE75316 validation cohorts. Analyses included functional enrichment, tumor microenvironment (TME) assessment (ESTIMATE, TIDE), immune correlation, and survival analysis. FLNA's cellular expression was delineated using single-cell RNA-seq data from 27,414 cells. Results FLNA was upregulated in advanced-stage CRC and exhibited diagnostic potential in microsatellite instability (MSI) samples. Pathway analysis revealed a significant enrichment of FLNA in biological processes implicated in cell adhesion and remodeling of the extracellular matrix. High FLNA expression correlated with an immunosuppressive microenvironment, characterized by elevated stromal/immune scores, increased cancer-associated fibroblast (CAF) and macrophage infiltration, and exclusion of CD8⁺ T cells. It also showed strong associations with multiple immune checkpoints. Single-cell transcriptomics confirmed specific, high FLNA expression in CAFs, fibroblasts, and endothelial cells, where it was associated with pro-tumorigenic functions, including actin cytoskeleton organization. Furthermore, FLNA emerged as an independent predictor of adverse outcomes and was independently associated with reduced overall survival (OS). Conclusion In summary, our findings suggest that FLNA expression is associated with tumor progression and an immunosuppressive microenvironment in CRC, and that FLNA warrants further investigation as a potential prognostic biomarker and therapeutic target.