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 (AEBP1), 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 AEBP1 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 AEBP1 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 AEBP1 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 AEBP1/ACLP to reduced CD8⁺ T-cell infiltration, our results suggest that stromal AEBP1/ACLP enhances both extracellular matrix stiffness and immune suppression and highlights AEBP1/ACLP as a potential therapeutic target through which to remodel the tumor microenvironment and improve anti-tumor immunity.