FATP5 loss in hepatocellular carcinoma cells orchestrates tumor-promoting microenvironment by inducing passive long-chain fatty acid accumulation within tumor-associated endothelial cells.

Hepatocellular carcinoma (HCC) is characterized by severe immunosuppression and metabolic reprogramming, yet the spatial dynamics of lipid flux between malignant and stromal cells remain poorly understood. Here, we identify a profound, type-specific metabolic rewiring in HCC driven by the widespread downregulation of fatty acid transport protein 5 (FATP5). FATP5 deficiency in malignant cells selectively attenuates the uptake of long-chain fatty acids (LCFAs), creating an extracellular lipid surplus that is passively sequestered by neighboring FATP3-expressing tumor-associated endothelial cells (TECs). Within TECs, accumulated LCFAs function as endogenous ligands that activate the nuclear receptor PPARγ, culminating in the robust transcriptional upregulation and paracrine secretion of the chemokine CXCL12. Endothelial-derived CXCL12 subsequently engages CXCR4 on infiltrating CD8+ T cells, inducing PD-1 expression and driving terminal T-cell exhaustion, thereby establishing an immunosuppressive niche that accelerates tumor progression. Importantly, our data suggest that HCC subtypes marked by FATP5 depletion and CXCL12+ TEC enrichment may possess potential therapeutic susceptibility to PPARγ antagonism or anti-PD-1 immune checkpoint blockade. Besides affecting the secretory function of TECs, accumulated LCFAs can impair endothelial barrier function, thereby creating a microenvironment with hematogenous metastasis risk. Collectively, our findings delineate a novel tumor-promoting microenvironment cascade orchestrated by LCFA spatial redistribution, providing a promising mechanistic foundation to support the future development of targeted precision interventions for FATP5-low HCC.