Long-Chain Fatty Acid Redistribution Induced by SLC27A2 Deficiency Facilitates Hypoxic Adaptation and Immunosuppression in Hepatocellular Carcinoma

Abstract Hypoxia, immune evasion, and metabolic reprogramming are key features of hepatocellular carcinoma (HCC) that limit the efficacy of therapies. Members of the solute carrier (SLC) family regulate metabolite homeostasis within tumor cells to maintain tumor survival under stressed conditions like hypoxia. Investigating the SLC family members could offer insights into the hypoxic microenvironment of HCC and potentially help identify improved therapeutic strategies. Here, we identified SLC27A2 as a hypoxia-responsive gene frequently downregulated in HCC, correlating with increased aggressiveness and adverse outcomes. HCC cells with low SLC27A2 expression exhibited enhanced hypoxia tolerance and resistance to hypoxia-related therapies, such as TACE and anti-angiogenic agents. Mechanistically, SLC27A2 downregulation led to reduced long-chain fatty acid (LCFA) intake, preventing LCFA accumulation under hypoxic conditions and mitigating cytotoxicity caused by lipid peroxidation. SLC27A2-deficient HCC cells were sensitive to glutaminase and fatty acid synthase inhibitors. The LCFAs in SLC27A2-deficient HCC were taken up by tumor-associated macrophages (TAMs), activating PPAR-γ transcriptional activity and promoting the enrichment of SPP1+ TAMs. Although this process led to immunosuppression, it presented an opportunity for applying anti-PD-1 therapy. In conclusion, the redistribution of LCFAs between HCC cells and TAMs, mediated by low SLC27A2 expression in cancer cells, supports adaptation to stress, promoting tumor progression and immunosuppression. The redistribution of LCFAs introduces molecular vulnerabilities and specific therapeutic opportunities for HCC.