CEBPG‐Mediated Palmitic Acid Adaptation of Cancer‐Associated Fibroblasts Drives Metastasis of Oral Squamous Cell Carcinoma

ABSTRACT Fatty acids (FAs) create a pro‐metastatic niche in multiple cancers, but how the tumor microenvironment (TME) counteracts FA stress remains unclear. Here, we found that the FA transporter CD36 was upregulated in myofibroblastic cancer‐associated fibroblasts (myoCAFs), where it correlated with the metastasis of oral squamous cell carcinoma (OSCC). Among five predominant FA species enriched in OSCC tissues, palmitic acid (PA) potently activated myoCAF phenotypes across 2D, 3D, and organoid co‐culture models. In vivo, PA promoted lymph node metastasis in orthotopic tumors comprising OSCC cells and CAFs, an effect abolished by CD36 knockdown in cancer‐associated fibroblasts (CAFs). Mechanistically, PA remodeled the chromatin landscape to enhance H3K27ac occupancy at multiple genes including ERN1 and TMBIM6 , two stress‐adaptive regulators. Transcription of ERN1 and TMBIM6 in CAFs was regulated by CCAAT/enhancer‐binding protein γ (CEBPG) in an enhancer‐associated manner. Disruption of the CEBPG‐IRE1α/TMBIM6 axis attenuated myoCAFs properties and abrogated PA‐driven metastasis. Our results unveil a stromal metabolic checkpoint and establish CEBPG‐mediated stress resilience as a therapeutic target to curtail metastasis. Significance: Palmitic acid promotes metastasis via a stromal CEBPG‐IRE1α/TMBIM6 axis, uncovering a metabolic vulnerability that offers novel therapeutic targets to inhibit oral squamous cell carcinoma.