CD276 promotes CD36-mediated lipid metabolism and confers resistance to tyrosine kinase inhibitors

The efficacy of tyrosine kinase inhibitor (TKI)-based systemic therapy in advanced hepatocellular carcinoma (HCC) is often limited by drug resistance, the mechanisms of which remain incompletely understood. Here, we demonstrate that CD276, an immune checkpoint protein, promotes TKI resistance in HCC by reprogramming lipid metabolism. Upon TKI treatment, CD276 binds pSTAT3 and undergoes importin α/β-dependent nuclear translocation. In the nucleus, CD276 cooperates with STAT3 to promote CD36 transcription, thereby potentiating fatty acid uptake, lipid droplet accumulation, and mitochondrial fatty acid β-oxidation. This metabolic rewiring drives HCC proliferation and confers TKI resistance. Importantly, pharmacological inhibition of CD36 with sulfosuccinimidyl oleate sodium suppresses fatty acid uptake and tumor lipid metabolism, resensitizing resistant HCC cells to TKIs. Our findings reveal the CD276-STAT3-CD36 axis as a key regulator of lipid metabolic reprogramming in TKI resistance, providing a promising therapeutic target to overcome treatment resistance in HCC.