Metabolic changes play a crucial role in determining the status and function of macrophages,but how lipid reprogramming in macrophages contributes to tumor progression is not yet fully understood.Here,we investigated ...Metabolic changes play a crucial role in determining the status and function of macrophages,but how lipid reprogramming in macrophages contributes to tumor progression is not yet fully understood.Here,we investigated the phenotype,contribution,and regulatory mechanisms of lipid droplet(LD)-laden macrophages(LLMs)in hepatocellular carcinoma(HCC).Enriched LLMs were found in tumor tissues and were associated with disease progression in HCC patients.The LLMs displayed immunosuppressive phenotypes(with extensive expression of TREM2,PD-L1,CD206,and CD163)and attenuated the antitumor activities of CD8^(+)T cells.Mechanistically,tumor-induced reshuffling of cellular lipids and TNFα-mediated uptake of tumoral fatty acids contribute to the generation of triglycerides and LDs in macrophages.LDs prolong LLM survival and promote CCL20 secretion,which further recruits CCR6^(+)Tregs to HCC tissue.Inhibiting LLM formation by targeting DGAT1 and DGAT2,which catalyze the synthesis of triglycerides,significantly reduced Treg recruitment,and delayed tumor growth in a mouse hepatic tumor model.Our results reveal the suppressive phenotypes and mechanisms of LLM enrichment in HCC and suggest the therapeutic potential of targeting LLMs for HCC patients.展开更多
基金supported by project grants from the National Key R&D Program of China(2023YFA0915703)the Guangdong Basic and Applied Basic Research Foundation(2022A1515111205)+1 种基金the National Natural Science Foundation of China(32230034,82273296)the Open Fund Project of Guangdong Academy of Medical Sciences(YKY-KF202207).
文摘Metabolic changes play a crucial role in determining the status and function of macrophages,but how lipid reprogramming in macrophages contributes to tumor progression is not yet fully understood.Here,we investigated the phenotype,contribution,and regulatory mechanisms of lipid droplet(LD)-laden macrophages(LLMs)in hepatocellular carcinoma(HCC).Enriched LLMs were found in tumor tissues and were associated with disease progression in HCC patients.The LLMs displayed immunosuppressive phenotypes(with extensive expression of TREM2,PD-L1,CD206,and CD163)and attenuated the antitumor activities of CD8^(+)T cells.Mechanistically,tumor-induced reshuffling of cellular lipids and TNFα-mediated uptake of tumoral fatty acids contribute to the generation of triglycerides and LDs in macrophages.LDs prolong LLM survival and promote CCL20 secretion,which further recruits CCR6^(+)Tregs to HCC tissue.Inhibiting LLM formation by targeting DGAT1 and DGAT2,which catalyze the synthesis of triglycerides,significantly reduced Treg recruitment,and delayed tumor growth in a mouse hepatic tumor model.Our results reveal the suppressive phenotypes and mechanisms of LLM enrichment in HCC and suggest the therapeutic potential of targeting LLMs for HCC patients.
