Suppression of macrophage membrane cholesterol efflux by SLAMF7-induced IL-7 signaling improves immunotherapy efficacy in hepatocellular carcinoma

Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma Nat Rev Dis Primers. 2021;7:6

Article  PubMed  Google Scholar 

Chen C, Wang Z, Ding Y, Qin Y. Tumor microenvironment-mediated immune evasion in hepatocellular carcinoma. Front Immunol. 2023;14: 1133308

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hu J, Liu N, Song D, Steer CJ, Zheng G, Song G. A positive feedback between cholesterol synthesis and the pentose phosphate pathway rather than glycolysis promotes hepatocellular carcinoma. Oncogene. 2023;42:2892–2904

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wan S, He QY, Yang Y, Liu F, Zhang X, Guo X, et al. SPARC stabilizes ApoE to induce cholesterol-dependent invasion and sorafenib resistance in hepatocellular carcinoma. Cancer Res. 2024;84(11):1872–1888

Article  CAS  PubMed  Google Scholar 

Pan Y, Chen H, Zhang X, Liu W, Ding Y, Huang D, et al. METTL3 drives NAFLD-related hepatocellular carcinoma and is a therapeutic target for boosting immunotherapy. Cell Rep Med. 2023;4: 101144

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tang W, Zhou J, Yang W, Feng Y, Wu H, Mok MTS, et al. Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver. Cell Mol Immunol. 2022;19:834–847

Article  CAS  PubMed  PubMed Central  Google Scholar 

Li Z, Wang Y, Xing R, Zeng H, Yu XJ, Zhang YJ, et al. Cholesterol efflux drives the generation of immunosuppressive macrophages to promote the progression of human hepatocellular carcinoma. Cancer Immunol Res. 2023;11:1400–1413

Article  CAS  PubMed  Google Scholar 

Wang J, Liu C, Hu R, Wu L, Li C. Statin therapy: a potential adjuvant to immunotherapies in hepatocellular carcinoma. Front Pharmacol. 2024;15: 1324140

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cachot A, Bilous M, Liu YC, Li X, Saillard M, Cenerenti M, et al. Tumor-specific cytolytic CD4 T cells mediate immunity against human cancer. Sci Adv. 2021. https://doi.org/10.1126/sciadv.abe3348

Article  PubMed  PubMed Central  Google Scholar 

Chen J, Zhong MC, Guo H, Davidson D, Mishel S, Lu Y, et al. SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via Mac-1 integrin. Nature. 2017;544:493–497

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mai EK, Goldschmid H, Miah K, Bertsch U, Besemer B, Hänel M, et al. Elotuzumab, lenalidomide, bortezomib, dexamethasone, and autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GMMG-HD6): results from a randomised, phase 3 trial. Lancet Haematol. 2024;11:e101–e113

Article  CAS  PubMed  Google Scholar 

Wang SH, Chou WC, Huang HC, Lee TA, Hsiao TC, Wang LH, et al. Deglycosylation of SLAMF7 in breast cancers enhances phagocytosis. Am J Cancer Res. 2022;12:4721–4736

CAS  PubMed  PubMed Central  Google Scholar 

Weng J, Wang Z, Hu Z, Xu W, Sun JL, Wang F, et al. Repolarization of immunosuppressive macrophages by targeting SLAMF7-regulated CCL2 signaling sensitizes hepatocellular carcinoma to immunotherapy. Cancer Res. 2024;84(11):1817–1833

Article  CAS  PubMed  Google Scholar 

Goossens P, Rodriguez-Vita J, Etzerodt A, Masse M, Rastoin O, Gouirand V, et al. Membrane cholesterol efflux drives tumor-associated macrophage reprogramming and tumor progression. Cell Metab. 2019;29:1376–89.e4

Article  CAS  PubMed  Google Scholar 

Cui D, Yu X, Guan Q, Shen Y, Liao J, Liu Y, et al. Cholesterol metabolism: molecular mechanisms, biological functions, diseases, and therapeutic targets. Mol Biomed. 2025;6:72

Article  CAS  PubMed  PubMed Central  Google Scholar 

Scott NA, Sharpe LJ, Capell-Hattam IM, Gullo SJ, Luu W, Brown AJ. The cholesterol synthesis enzyme lanosterol 14α-demethylase is post-translationally regulated by the E3 ubiquitin ligase MARCH6. Biochem J. 2020;477:541–555

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tamarit B, Bugault F, Pillet AH, Lavergne V, Bochet P, Garin N, et al. Membrane microdomains and cytoskeleton organization shape and regulate the IL-7 receptor signalosome in human CD4 T-cells. J Biol Chem. 2013;288:8691–8701

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ma L, Hernandez MO, Zhao Y, Mehta M, Tran B, Kelly M, et al. Tumor cell biodiversity drives microenvironmental reprogramming in liver cancer. Cancer Cell. 2019;36:418–30.e6

Article  CAS  PubMed  PubMed Central  Google Scholar 

Asadi Y, Moundounga RK, Chakroborty A, Pokokiri A, Wang H. FOXOs and their roles in acute and chronic neurological disorders. Front Mol Biosci. 2025;12:1538472

Article  CAS  PubMed  PubMed Central  Google Scholar 

Xu R, Song J, Ruze R, Chen Y, Yin X, Wang C, et al. SQLE promotes pancreatic cancer growth by attenuating ER stress and activating lipid rafts-regulated Src/PI3K/Akt signaling pathway. Cell Death Dis. 2023;14:497

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rashkovan M, Albero R, Gianni F, Perez-Duran P, Miller HI, Mackey AL, et al. Intracellular cholesterol pools regulate oncogenic signaling and epigenetic circuitries in early T-cell precursor acute lymphoblastic leukemia. Cancer Discov. 2022;12:856–871

Article  CAS  PubMed  PubMed Central  Google Scholar 

Laguna-Maldonado KD, Uribe-Ramírez D, Vázquez-Carrada M, Matuz-Mares D, Vilchis-Landeros MM. Dysfunction of the ABCA1 and ABCG1 transporters and their impact on HDL metabolism. Antioxidants Basel. 2025. https://doi.org/10.3390/antiox14111362

Article  PubMed  PubMed Central  Google Scholar 

Du D, Liu C, Qin M, Zhang X, Xi T, Yuan S, et al. Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma. Acta Pharm Sin B. 2022;12:558–580

Article  CAS  PubMed  Google Scholar 

Mossmann D, Müller C, Park S, Ryback B, Colombi M, Ritter N, et al. Arginine reprograms metabolism in liver cancer via RBM39. Cell. 2023;186:5068–83.e23

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature. 2016;531:253–257

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wu Y, Wang Q, Li M, Lao J, Tang H, Ming S, et al. SLAMF7 regulates the inflammatory response in macrophages during polymicrobial sepsis. J Clin Invest. 2023. https://doi.org/10.1172/JCI150224

Article  PubMed  PubMed Central  Google Scholar 

Luo G, Ni R, Huang X, Li Y, Luo D. The role of signaling lymphocytic activation molecule (SLAM) family receptors in health and disease progression: focusing on cancer and therapy. Clin Immunol. 2025;280: 110574

Article  CAS  PubMed  Google Scholar 

Tang XE, Li H, Chen LY, Xia XD, Zhao ZW, Zheng XL, et al. IL-8 negatively regulates ABCA1 expression and cholesterol efflux via upregulating miR-183 in THP-1 macrophage-derived foam cells. Cytokine. 2019;122: 154385

Article  CAS  PubMed 

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