Speaker
Description
Background: Hepatocellular carcinoma (HCC) is characterized by hypervascularity and profound resistance to current anti-angiogenic therapies. Endothelial metabolic reprogramming is recognized as a critical driver of tumor angiogenesis, yet the key metabolic regulators within tumor endothelial cells (TECs) in HCC remain largely unknown. This study aims to identify these regulators and elucidate their roles in vascular remodeling and antitumor immunity.
Methods: Single-cell RNA sequencing and HCC cohort validation identified key metabolic regulators in TECs. EC-specific Cd36 knockout mice (Cd36 EC-KO) were generated, and therapeutic potential was evaluated via an endothelial-specific adeno-associated virus (AAV-Tie2-Cd36). Sulfo-N-succinimidyl oleate (SSO) inhibition and EC untargeted metabolomics were used to investigate lipid transport and metabolic mechanisms.
Results: CD36 was the most downregulated metabolic gene in TECs. Cd36 EC-KO accelerated spontaneous liver tumor growth and metastasis versus WT mice, with increased vessel density, impaired maturation (α-SMA coverage), and decreased CD8⁺ T cell infiltration. SSO inhibition confirmed that CD36’s tumor suppression depends on lipid transport. Mechanistically, CD36 enriches long-chain unsaturated fatty acids in ECs; its loss triggers metabolic remodeling that promotes pathological angiogenesis and impairs CD8⁺ T cell recruitment via silencing VCAM1/ICAM1. Endothelial CD36 restoration via AAV-Tie2-Cd36 normalized vasculature, boosted antitumor immunity, and inhibited tumor progression.
Conclusions: Endothelial CD36 is a critical metabolic tumor suppressor orchestrating the HCC immune microenvironment. Loss of CD36 triggers metabolic reprogramming that drives pathological angiogenesis and impairs CD8⁺ T cell recruitment. Our results provide new insights into endothelial metabolism-immunity interplay. Targeting the CD36-fatty acid axis promotes vascular normalization and synergizes with HCC immunotherapy.
