Metabolic adaptation of stromal cells to fatty acid drives metastasis of oral squamous cell carcinoma

Metabolic adaptation enables cancer cell survival under nutrient stress, but how stromal cells in tumor microenvironment (TME) withstand similar metabolic change remains elusive. Here, we report that fatty acids (FAs), a nutrient with dual roles in energy provision and lipotoxicity, orchestrate a pro-metastatic adaptation program in cancer-associated fibroblasts (CAFs). In patients with oral squamous cell carcinoma (OSCC), the FA transporter CD36 was upregulated not only in cancer cells but also in myofibroblastic CAFs (myoCAFs), where it correlated with more advanced metastasis stage. Among 5 kinds of FAs enriched in OSCC tissues, palmitic acid (PA) potently activated myoCAFs 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 CAFs. Mechanistically, PA engaged chromatin occupancy of H3K27ac at multiple genes including IRE1 and TMBIM6, two stress-adaptive regulators. Transcription of IRE1 and TMBIM6 in CAFs was regulated by CCAAT/enhancer-binding protein γ (CEBPG) through an enhancer-dependent manner. Disruption of the CEBPG–IRE1/TMBIM6 axis attenuated myoCAFs properties and abrogated PA-driven metastasis. Our results unveil a stromal metabolic checkpoint and establish CEBPG-enhanced stress resilience as a therapeutic target to curtail metastasis.