Metabolism archetype cancer cells induce protumor TREM2+ macrophages via oxLDL-mediated metabolic interplay in hepatocellular carcinoma
Abstract The functional programs adopted by cancer cells and their impact on the tumor microenvironment are complex and remain unclear. Here, we identify three distinct single-cell archetypes (i.e. metabolism, stemness and inflammation) in hepatocellular carcinoma (HCC) cells, each exhibiting unique...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-62132-y |
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| author | Tianhao Chu Guiqi Zhu Zheng Tang Weifeng Qu Rui Yang Haiting Pan Yi Wang Ruilin Tian Leilei Chen Zhiqi Guan Yichao Bu Qianfu Zhao Jiafeng Chen Shengwei Mao Yuan Fang Jun Gao Xiaoling Wu Jian Zhou Weiren Liu Dan Ye Jia Fan Yinghong Shi |
| author_facet | Tianhao Chu Guiqi Zhu Zheng Tang Weifeng Qu Rui Yang Haiting Pan Yi Wang Ruilin Tian Leilei Chen Zhiqi Guan Yichao Bu Qianfu Zhao Jiafeng Chen Shengwei Mao Yuan Fang Jun Gao Xiaoling Wu Jian Zhou Weiren Liu Dan Ye Jia Fan Yinghong Shi |
| author_sort | Tianhao Chu |
| collection | DOAJ |
| description | Abstract The functional programs adopted by cancer cells and their impact on the tumor microenvironment are complex and remain unclear. Here, we identify three distinct single-cell archetypes (i.e. metabolism, stemness and inflammation) in hepatocellular carcinoma (HCC) cells, each exhibiting unique spatial distribution. Further analysis shows an immune-suppressive niche populated by metabolism archetype cancer cells and TREM2-positive tumor-associated macrophages (TREM2+ TAMs), which exacerbates immune exclusion and compromises patient outcomes. Mechanistically, we demonstrate that the upregulated squalene epoxidase (SQLE) expression in metabolism archetype cancer cells facilitates the generation of oxidized LDL (oxLDL). OxLDL induces TREM2+ TAM polarization through the TREM2-SYK-CEBPα axis, enabling these TAMs to promote cancer cell invasion, resistance to effector cytokines and CD8+ T cell dysfunction. Importantly, cancer cell-intrinsic SQLE and TREM2+ TAMs are associated with inferior immunotherapy response in human and mouse HCC. Our results highlight an oxLDL-mediated metabolic interplay between cancer cells and TREM2+ TAMs, offering a promising therapeutic avenue for HCC immunotherapies. |
| format | Article |
| id | doaj-art-1ca5481dc15e43f4a03eb680170cf054 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-1ca5481dc15e43f4a03eb680170cf0542025-08-20T04:03:02ZengNature PortfolioNature Communications2041-17232025-07-0116112510.1038/s41467-025-62132-yMetabolism archetype cancer cells induce protumor TREM2+ macrophages via oxLDL-mediated metabolic interplay in hepatocellular carcinomaTianhao Chu0Guiqi Zhu1Zheng Tang2Weifeng Qu3Rui Yang4Haiting Pan5Yi Wang6Ruilin Tian7Leilei Chen8Zhiqi Guan9Yichao Bu10Qianfu Zhao11Jiafeng Chen12Shengwei Mao13Yuan Fang14Jun Gao15Xiaoling Wu16Jian Zhou17Weiren Liu18Dan Ye19Jia Fan20Yinghong Shi21Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationEndoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan UniversityDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationMolecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan UniversityMolecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan UniversityDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationMolecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan UniversityDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationDepartment of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of EducationAbstract The functional programs adopted by cancer cells and their impact on the tumor microenvironment are complex and remain unclear. Here, we identify three distinct single-cell archetypes (i.e. metabolism, stemness and inflammation) in hepatocellular carcinoma (HCC) cells, each exhibiting unique spatial distribution. Further analysis shows an immune-suppressive niche populated by metabolism archetype cancer cells and TREM2-positive tumor-associated macrophages (TREM2+ TAMs), which exacerbates immune exclusion and compromises patient outcomes. Mechanistically, we demonstrate that the upregulated squalene epoxidase (SQLE) expression in metabolism archetype cancer cells facilitates the generation of oxidized LDL (oxLDL). OxLDL induces TREM2+ TAM polarization through the TREM2-SYK-CEBPα axis, enabling these TAMs to promote cancer cell invasion, resistance to effector cytokines and CD8+ T cell dysfunction. Importantly, cancer cell-intrinsic SQLE and TREM2+ TAMs are associated with inferior immunotherapy response in human and mouse HCC. Our results highlight an oxLDL-mediated metabolic interplay between cancer cells and TREM2+ TAMs, offering a promising therapeutic avenue for HCC immunotherapies.https://doi.org/10.1038/s41467-025-62132-y |
| spellingShingle | Tianhao Chu Guiqi Zhu Zheng Tang Weifeng Qu Rui Yang Haiting Pan Yi Wang Ruilin Tian Leilei Chen Zhiqi Guan Yichao Bu Qianfu Zhao Jiafeng Chen Shengwei Mao Yuan Fang Jun Gao Xiaoling Wu Jian Zhou Weiren Liu Dan Ye Jia Fan Yinghong Shi Metabolism archetype cancer cells induce protumor TREM2+ macrophages via oxLDL-mediated metabolic interplay in hepatocellular carcinoma Nature Communications |
| title | Metabolism archetype cancer cells induce protumor TREM2+ macrophages via oxLDL-mediated metabolic interplay in hepatocellular carcinoma |
| title_full | Metabolism archetype cancer cells induce protumor TREM2+ macrophages via oxLDL-mediated metabolic interplay in hepatocellular carcinoma |
| title_fullStr | Metabolism archetype cancer cells induce protumor TREM2+ macrophages via oxLDL-mediated metabolic interplay in hepatocellular carcinoma |
| title_full_unstemmed | Metabolism archetype cancer cells induce protumor TREM2+ macrophages via oxLDL-mediated metabolic interplay in hepatocellular carcinoma |
| title_short | Metabolism archetype cancer cells induce protumor TREM2+ macrophages via oxLDL-mediated metabolic interplay in hepatocellular carcinoma |
| title_sort | metabolism archetype cancer cells induce protumor trem2 macrophages via oxldl mediated metabolic interplay in hepatocellular carcinoma |
| url | https://doi.org/10.1038/s41467-025-62132-y |
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