Pan-Cancer Analysis Reveals AEBP1-Collagen Co-Expression and Its Potential Role in CAF-Mediated Tumor Stiffness

Cancer-associated fibroblasts (CAFs) are critical components of the tumor microenvironment that promote cancer progression and immune evasion. Adipocyte enhancer-binding protein 1 gene (<i>AEBP1</i>), which encodes aortic carboxypeptidase-like protein (ACLP), has been implicated in tissue remodeling and fibrosis, yet its role in CAF biology across cancers remains poorly understood. Here, we performed a pan-cancer transcriptomic analysis using The Cancer Genome Atlas (TCGA) and found that <i>AEBP1</i> expression strongly correlates with expression of collagen family genes in the majority of solid tumors. Integration of single-cell RNA-sequencing datasets from breast and pancreatic cancers revealed that <i>AEBP1</i> is predominantly expressed in CAFs, where it is co-expressed with collagens and CAF marker genes. Functional experiments using three-dimensional (3D) spheroids composed of oral squamous cell carcinoma (OSCC)-derived CAFs showed that <i>AEBP1</i> knockdown significantly reduced spheroid stiffness without altering their morphology or size, indicating that ACLP contributes to the mechanical properties of tumor tissues. Together with earlier findings linking <i>AEBP1</i>/ACLP to reduced CD8⁺ T-cell infiltration, our results suggest that stromal <i>AEBP1</i>/ACLP enhances both extracellular matrix stiffness and immune suppression and highlights <i>AEBP1</i>/ACLP as a potential therapeutic target through which to remodel the tumor microenvironment and improve anti-tumor immunity.