Diverse immunological roles of liver-resident immune cells in liver diseases

Abstract

The liver immune microenvironment is a complex system regulated by the interaction between circulating immune cells and resident immune cell populations. In recent years, liver resident immune cells (LRICs) have received increasing attention as an important cell population for regulating liver pathology. These types of non-circulating liver cells have unique adaptability, not only meeting the metabolic needs of the liver but also maintaining its immune homeostasis. The advancement of high-throughput technology has enabled in-depth research on the unique origin, developmental pathways, and functional plasticity of LRICs. LRICs can initiate rapid, strong, and long-lasting tissue-specific immune responses to effectively curb disease progression. However, these powerful abilities may translate into pathogenic factors in specific situations: triggering tissue damage in the autoimmune environment and mediating graft rejection after liver transplantation. This article systematically reviews the current understanding of these key resident immune cell populations, details their multidimensional and often paradoxical mechanisms of action in a variety of major liver pathologies, and discusses the prospects of emerging therapeutic strategies for these key cell players.

Keywords

diverse immunological roles / immunity / liver diseases / liver-resident immune cells / therapy

References

[1] Kubes P, Jenne C. Immune responses in the liver. Annu Rev Immunol. 2018; 36: 247-277.

[2] Cheng ML, Nakib D, Perciani CT, MacParland SA. The immune niche of the liver. Clin Sci (Lond). 2021; 135(20): 2445-2466.

[3] Zhao J, Zhang S, Liu Y, et al. Single-cell RNA sequencing reveals the heterogeneity of liver-resident immune cells in human. Cell Discov. 2020; 6: 22.

[4] Li X, Li S, Wu B, et al. Landscape of immune cells heterogeneity in liver transplantation by single-cell RNA sequencing analysis. Front Immunol. 2022; 13:890019.

[5] Pang W, Wang Y, Lu X, et al. Integrated spatial and single cell transcriptomics identifies PRKDC as a dual prognostic biomarker and therapeutic target in hepatocellular carcinoma. Sci Rep. 2025; 15(1):14834.

[6] Wang J, Li Q, Qiu Y, et al. Cell-type-specific expression analysis of liver transcriptomics with clinical parameters to decipher the cause of intrahepatic inflammation in chronic hepatitis B. Imeta. 2024; 3(4):e221.

[7] Guilliams M, Bonnardel J, Haest B, et al. Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches. Cell. 2022; 185(2): 379-396.e38.

[8] Qi J, Yan X, Li L, Qiu K, Huang W, Zhou Z. CXCL5 promotes lipotoxicity of hepatocytes through upregulating NLRP3/Caspase-1/IL-1β signaling in Kupffer cells and exacerbates nonalcoholic steatohepatitis in mice. Int Immunopharmacol. 2023; 123:110752.

[9] Yu Y, Liu Y, An W, Song J, Zhang Y, Zhao X. STING-mediated inflammation in Kupffer cells contributes to progression of nonalcoholic steatohepatitis. J Clin Invest. 2019; 129(2): 546-555.

[10] Wang J, Leclercq I, Brymora JM, et al. Kupffer cells mediate leptin-induced liver fibrosis. Gastroenterology. 2009; 137(2): 713-723.

[11] Simón-Codina B, Cacho-Pujol J, Moles A, Melgar-Lesmes P. Reprogramming macrophages to treat liver diseases. Hepatology. 2024.

[12] Yao JM, Ying HZ, Zhang HH, Qiu FS, Wu JQ, Yu CH. Exosomal RBP4 potentiated hepatic lipid accumulation and inflammation in high-fat-diet-fed mice by promoting M1 polarization of Kupffer cells. Free Radic Biol Med. 2023; 195: 58-73.

[13] Bradić I, Kuentzel KB, Pirchheim A, et al. From LAL-D to MASLD: insights into the role of LAL and Kupffer cells in liver inflammation and lipid metabolism. Biochim Biophys Acta Mol Cell Biol Lipids. 2025; 1870(1):159575.

[14] Blériot C, Barreby E, Dunsmore G, et al. A subset of Kupffer cells regulates metabolism through the expression of CD36. Immunity. 2021; 54(9): 2101-2116.e6.

[15] Luo P, Wang F, Wong NK, et al. Divergent roles of Kupffer cell TLR2/3 signaling in alcoholic liver disease and the protective role of EGCG. Cell Mol Gastroenterol Hepatol. 2020; 9(1): 145-160.

[16] Pan XS, Li BW, Wang LL, et al. Kupffer cell pyroptosis mediated by METTL3 contributes to the progression of alcoholic steatohepatitis. FASEB J. 2023; 37(6):e22965.

[17] Wang C, Zai W, Zhao K, et al. Potential role of liver-resident CD3(+) macrophages in HBV clearance in a mouse hepatitis B model. JHEP Rep. 2025; 7(4):101323.

[18] Roca Suarez AA, Plissonnier ML, Grand X, et al. TLR8 agonist selgantolimod regulates Kupffer cell differentiation status and impairs HBV entry into hepatocytes via an IL-6-dependent mechanism. Gut. 2024; 73(12): 2012-2022.

[19] Li X, Li R, Miao X, et al. Integrated single cell analysis reveals an atlas of tumor associated macrophages in hepatocellular carcinoma. Inflammation. 2024; 47(6): 2077-2093.

[20] Liang S, Ma HY, Zhong Z, et al. NADPH oxidase 1 in liver macrophages promotes inflammation and tumor development in mice. Gastroenterology. 2019; 156(4): 1156-1172.e6.

[21] Yuan D, Huang S, Berger E, et al. Kupffer cell-derived Tnf triggers cholangiocellular tumorigenesis through JNK due to chronic mitochondrial dysfunction and ROS. Cancer Cell. 2017; 31(6): 771-789.e6.

[22] Sun K, Xu L, Jing Y, et al. Autophagy-deficient Kupffer cells promote tumorigenesis by enhancing mtROS-NF-κB-IL1α/β-dependent inflammation and fibrosis during the preneoplastic stage of hepatocarcinogenesis. Cancer Lett. 2017; 388: 198-207.

[23] Lavin Y, Winter D, Blecher-Gonen R, et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell. 2014; 159(6): 1312-1326.

[24] Jiang P, Luo L, Li X, et al. PTX3 exacerbates hepatocyte pyroptosis in hepatic ischemia-reperfusion injury by promoting macrophage M1 polarization. Int Immunopharmacol. 2024; 143(Pt 3):113604.

[25] Wang C, Ma C, Gong L, et al. Macrophage polarization and its role in liver disease. Front Immunol. 2021; 12:803037.

[26] Cao S, Liu M, Sehrawat TS, Shah VH. Regulation and functional roles of chemokines in liver diseases. Nat Rev Gastroenterol Hepatol. 2021; 18(9): 630-647.

[27] Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology. 2014; 147(3): 577-594.e1.

[28] Cai P, Ni R, Lv M, et al. VEGF signaling governs the initiation of biliary-mediated liver regeneration through the PI3K-mTORC1 axis. Cell Rep. 2023; 42(9):113028.

[29] Soleiman-Meigooni S, Yarahmadi A, Kheirkhah AH, Afkhami H. Recent advances in different interactions between toll-like receptors and hepatitis B infection: a review. Front Immunol. 2024; 15:1363996.

[30] Hammerich L, Tacke F. Hepatic inflammatory responses in liver fibrosis. Nat Rev Gastroenterol Hepatol. 2023; 20(10): 633-646.

[31] Boltjes A, Movita D, Boonstra A, Woltman AM. The role of Kupffer cells in hepatitis B and hepatitis C virus infections. J Hepatol. 2014; 61(3): 660-671.

[32] Hakeem AN, Kamal MM, Tawfiq RA, et al. Elafibranor modulates ileal macrophage polarization to restore intestinal integrity in NASH: potential crosstalk between ileal IL-10/STAT3 and hepatic TLR4/NF-κB axes. Biomed Pharmacother. 2023; 157:114050.

[33] Wang Z, Du K, Jin N, Tang B, Zhang W. Macrophage in liver fibrosis: identities and mechanisms. Int Immunopharmacol. 2023; 120:110357.

[34] Ramachandran P, Pellicoro A, Vernon MA, et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc Natl Acad Sci U S A. 2012; 109(46): E3186-E3195.

[35] Uchinami H, Seki E, Brenner DA, D'Armiento J. Loss of MMP 13 attenuates murine hepatic injury and fibrosis during cholestasis. Hepatology. 2006; 44(2): 420-429.

[36] Fallowfield JA, Mizuno M, Kendall TJ, et al. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol. 2007; 178(8): 5288-5295.

[37] Wenes M, Shang M, Di Matteo M, et al. Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab. 2016; 24(5): 701-715.

[38] Ramirez-Pedraza M, Fernández M. Interplay between macrophages and angiogenesis: a double-edged sword in liver disease. Front Immunol. 2019; 10:2882.

[39] Shiau DJ, Kuo WT, Davuluri GVN, et al. Hepatocellular carcinoma-derived high mobility group box 1 triggers M2 macrophage polarization via a TLR2/NOX2/autophagy axis. Sci Rep. 2020; 10(1):13582.

[40] Wang H, Herman A, Barrow F, et al. Single-cell RNA sequencing reveals a reprogramming of hepatic immune cells and a protective role for B cells in MASH-driven HCC. Hepatol Commun. 2025; 9(5).

[41] Pallett LJ, Maini MK. Liver-resident memory T cells: life in lockdown. Semin Immunopathol. 2022; 44(6): 813-825.

[42] Masopust D, Soerens AG. Tissue-resident T cells and other resident leukocytes. Annu Rev Immunol. 2019; 37: 521-546.

[43] You Z, Li Y, Wang Q, et al. The clinical significance of hepatic CD69(+) CD103(+) CD8(+) resident-memory T cells in autoimmune hepatitis. Hepatology. 2021; 74(2): 847-863.

[44] Zimmer CL, von Seth E, Buggert M, et al. A biliary immune landscape map of primary sclerosing cholangitis reveals a dominant network of neutrophils and tissue-resident T cells. Sci Transl Med. 2021; 13(599).

[45] Dudek M, Pfister D, Donakonda S, et al. Auto-aggressive CXCR6(+) CD8 T cells cause liver immune pathology in NASH. Nature. 2021; 592(7854): 444-449.

[46] Li Y, You Z, Tang R, Ma X. Tissue-resident memory T cells in chronic liver diseases: phenotype, development and function. Front Immunol. 2022; 13:967055.

[47] Wang Y, Li X, Shan J, Ding R, Cai J. Unraveling the role of anoikis in non-alcoholic fatty liver disease progression and immune cell infiltration. Life Conflux. 2025; 1(2):e129.

[48] Koda Y, Teratani T, Chu PS, et al. CD8(+) tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells. Nat Commun. 2021; 12(1):4474.

[49] Cheng Y, Gunasegaran B, Singh HD, et al. Non-terminally exhausted tumor-resident memory HBV-specific T cell responses correlate with relapse-free survival in hepatocellular carcinoma. Immunity. 2021; 54(8): 1825-1840.e7.

[50] Pallett LJ, Davies J, Colbeck EJ, et al. IL-2(high) tissue-resident T cells in the human liver: sentinels for hepatotropic infection. J Exp Med. 2017; 214(6): 1567-1580.

[51] Barsch M, Salié H, Schlaak AE, et al. T-cell exhaustion and residency dynamics inform clinical outcomes in hepatocellular carcinoma. J Hepatol. 2022; 77(2): 397-409.

[52] Lim CJ, Lee YH, Pan L, et al. Multidimensional analyses reveal distinct immune microenvironment in hepatitis B virus-related hepatocellular carcinoma. Gut. 2019; 68(5): 916-927.

[53] Liu L, Liu J, Li P, et al. Single-cell analysis reveals HBV-specific PD-1(+)CD8(+) TRM cells in tumor borders are associated with HBV-related hepatic damage and fibrosis in HCC patients. J Exp Clin Cancer Res. 2023; 42(1):152.

[54] Zhang JM, Huang H, Li XQ, et al. FLT3(+) DC inhibits immune rejection via interaction with Treg in liver transplantation. Int Immunopharmacol. 2024; 137:112289.

[55] Zhou LX, Jiang YZ, Li XQ, et al. Myeloid-derived suppressor cells-induced exhaustion of CD8 + T-cell participates in rejection after liver transplantation. Cell Death Dis. 2024; 15(7):507.

[56] Sensi B, Angelico R, Toti L, et al. Mechanism, potential, and concerns of immunotherapy for hepatocellular carcinoma and liver transplantation. Curr Mol Pharmacol. 2024; 17:e18761429310703.

[57] Pallett LJ, Burton AR, Amin OE, et al. Longevity and replenishment of human liver-resident memory T cells and mononuclear phagocytes. J Exp Med. 2020; 217(9).

[58] Li X, Li S, Wang Y, et al. Single cell RNA-sequencing delineates CD8(+) tissue resident memory T cells maintaining rejection in liver transplantation. Theranostics. 2024; 14(12): 4844-4860.

[59] Zhao N, Dang H, Ma L, et al. Intratumoral γδ T-cell infiltrates, chemokine (C-C motif) ligand 4/chemokine (C-C motif) ligand 5 protein expression and survival in patients with hepatocellular carcinoma. Hepatology. 2021; 73(3): 1045-1060.

[60] Rha MS, Han JW, Koh JY, et al. Impaired antibacterial response of liver sinusoidal Vγ9(+)Vδ2(+) T cells in patients with chronic liver disease. Gut. 2022; 71(3): 605-615.

[61] He W, Hu Y, Chen D, et al. Hepatocellular carcinoma-infiltrating γδ T cells are functionally defected and allogenic Vδ2(+) γδ T cell can be a promising complement. Clin Transl Med. 2022; 12(4):e800.

[62] Marinović S, Lenartić M, Mladenić K, et al. NKG2D-mediated detection of metabolically stressed hepatocytes by innate-like T cells is essential for initiation of NASH and fibrosis. Sci Immunol. 2023; 8(87):eadd1599.

[63] Liu Q, Yang Q, Wu Z, et al. IL-1β-activated mTORC2 promotes accumulation of IFN-γ(+) γδ T cells by upregulating CXCR3 to restrict hepatic fibrosis. Cell Death Dis. 2022; 13(4):289.

[64] Rha MS, Han JW, Kim JH, et al. Human liver CD8(+) MAIT cells exert TCR/MR1-independent innate-like cytotoxicity in response to IL-15. J Hepatol. 2020; 73(3): 640-650.

[65] Mabire M, Hegde P, Hammoutene A, et al. MAIT cell inhibition promotes liver fibrosis regression via macrophage phenotype reprogramming. Nat Commun. 2023; 14(1):1830.

[66] Huang W, Ye D, He W, He X, Shi X, Gao Y. Activated but impaired IFN-γ production of mucosal-associated invariant T cells in patients with hepatocellular carcinoma. J Immunother Cancer. 2021; 9(11).

[67] Boulouis C, Leeansyah E, Mairpady Shambat S, Norrby-Teglund A, Sandberg JK. Mucosa-associated invariant T cell hypersensitivity to Staphylococcus aureus leukocidin ED and its modulation by activation. J Immunol. 2022; 208(5): 1170-1179.

[68] Xia Q, Lyu Z, Zhao Y, et al. The phenotypic and functional characteristics of intrahepatic CD69(+)CD103(+) tissue-resident MAIT cells in primary biliary cholangitis. J Autoimmun. 2025; 154:103442.

[69] Böttcher K, Rombouts K, Saffioti F, et al. MAIT cells are chronically activated in patients with autoimmune liver disease and promote profibrogenic hepatic stellate cell activation. Hepatology. 2018; 68(1): 172-186.

[70] Mehta H, Lett MJ, Klenerman P, Filipowicz Sinnreich M. MAIT cells in liver inflammation and fibrosis. Semin Immunopathol. 2022; 44(4): 429-444.

[71] Duan M, Goswami S, Shi JY, et al. Activated and exhausted MAIT cells foster disease progression and indicate poor outcome in hepatocellular carcinoma. Clin Cancer Res. 2019; 25(11): 3304-3316.

[72] Andreata F, Laura C, Ravà M, et al. Therapeutic potential of co-signaling receptor modulation in hepatitis B. Cell. 2024; 187(15): 4078-4094.e21.

[73] Ruf B, Bruhns M, Babaei S, et al. Tumor-associated macrophages trigger MAIT cell dysfunction at the HCC invasive margin. Cell. 2023; 186(17): 3686-3705.e32.

[74] Fu S, Liu M, Zhu C, et al. Regulatory mucosa-associated invariant T cells controlled by β1 adrenergic receptor signaling contribute to hepatocellular carcinoma progression. Hepatology. 2023; 78(1): 72-87.

[75] Zuyin L, Zhao L, Qian C, et al. Single-cell and spatial transcriptomics delineate the microstructure and immune landscape of intrahepatic cholangiocarcinoma in the leading-edge area. Adv Sci (Weinh). 2025; 12(7):e2412740.

[76] Bolte FJ, O'Keefe AC, Webb LM, et al. Intra-hepatic depletion of mucosal-associated invariant T cells in hepatitis C virus-induced liver inflammation. Gastroenterology. 2017; 153(5): 1392-1403.e2.

[77] Liu Y, Zhu P, Wang W, et al. Mucosal-associated invariant T cell dysregulation correlates with conjugated bilirubin level in chronic HBV infection. Hepatology. 2021; 73(5): 1671-1687.

[78] Wang H, Li L, Li Y, et al. Intravital imaging of interactions between iNKT and kupffer cells to clear free lipids during steatohepatitis. Theranostics. 2021; 11(5): 2149-2169.

[79] Cui K, Yan G, Xu C, et al. Invariant NKT cells promote alcohol-induced steatohepatitis through interleukin-1β in mice. J Hepatol. 2015; 62(6): 1311-1318.

[80] Song M, Wang H, Tian X, et al. TIPE2 protein restrains invariant NKT activation and protects against immune-mediated hepatitis in mice. Hepatology. 2025; 81(6): 1671-1684.

[81] Weng X, He Y, Visvabharathy L, et al. Crosstalk between type II NKT cells and T cells leads to spontaneous chronic inflammatory liver disease. J Hepatol. 2017; 67(4): 791-800.

[82] Tang W, Zhou J, Yang W, et al. Aberrant cholesterol metabolic signaling impairs antitumor immunosurveillance through natural killer T cell dysfunction in obese liver. Cell Mol Immunol. 2022; 19(7): 834-847.

[83] Ghanim M, Amer J, Salhab A, Jaradat N. Ecballium elaterium improved stimulatory effects of tissue-resident NK cells and ameliorated liver fibrosis in a thioacetamide mice model. Biomed Pharmacother. 2022; 150:112942.

[84] Cheng C, Zhang Q, Li Y, et al. Interplay between liver type 1 innate lymphoid cells and NK cells drives the development of alcoholic steatohepatitis. Cell Mol Gastroenterol Hepatol. 2023; 15(1): 261-274.

[85] Nabekura T, Riggan L, Hildreth AD, O'Sullivan TE, Shibuya A. Type 1 innate lymphoid cells protect mice from acute liver injury via interferon-γ secretion for upregulating Bcl-xL expression in hepatocytes. Immunity. 2020; 52(1): 96-108.e9.

[86] Fumagalli V, Venzin V, Di Lucia P, et al. Group 1 ILCs regulate T cell-mediated liver immunopathology by controlling local IL-2 availability. Sci Immunol. 2022; 7(68):eabi6112.

[87] Zhao ZB, Lu FT, Ma HD, et al. Liver-resident NK cells suppress autoimmune cholangitis and limit the proliferation of CD4(+) T cells. Cell Mol Immunol. 2020; 17(2): 178-189.

[88] Zhou J, Peng H, Li K, et al. Liver-resident NK cells control antiviral activity of hepatic T cells via the PD-1-PD-L1 axis. Immunity. 2019; 50(2): 403-417.e4.

[89] Narmada BC, Khakpoor A, Shirgaonkar N, et al. Single-cell landscape of functionally cured chronic hepatitis B patients reveals activation of innate and altered CD4-CTL-driven adaptive immunity. J Hepatol. 2024; 81(1): 42-61.

[90] Forrest C, Chase TJG, Cuff AO, et al. Control of human cytomegalovirus replication by liver resident natural killer cells. Nat Commun. 2023; 14(1):1409.

[91] Zhong HJ, Zhuang YP, Xie X, et al. Washed microbiota transplantation promotes homing of group 3 innate lymphoid cells to the liver via the CXCL16/CXCR6 axis: a potential treatment for metabolic-associated fatty liver disease. Gut Microbes. 2024; 16(1):2372881.

[92] Yang L, Zhang Y, Wang L, et al. Amelioration of high fat diet induced liver lipogenesis and hepatic steatosis by interleukin-22. J Hepatol. 2010; 53(2): 339-347.

[93] Hamaguchi M, Okamura T, Fukuda T, et al. Group 3 innate lymphoid cells protect steatohepatitis from high-fat diet induced toxicity. Front Immunol. 2021; 12:648754.

[94] Mackay LK, Minnich M, Kragten NA, et al. Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes. Science. 2016; 352(6284): 459-463.

[95] Zhao J, Chen X, Herjan T, Li X. The role of interleukin-17 in tumor development and progression. J Exp Med. 2020; 217(1).

[96] Liu Y, Song Y, Lin D, et al. NCR(−) group 3 innate lymphoid cells orchestrate IL-23/IL-17 axis to promote hepatocellular carcinoma development. EBioMedicine. 2019; 41: 333-344.

[97] Jiang R, Tan Z, Deng L, et al. Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology. 2011; 54(3): 900-909.

[98] Park O, Wang H, Weng H, et al. In vivo consequences of liver-specific interleukin-22 expression in mice: implications for human liver disease progression. Hepatology. 2011; 54(1): 252-261.

[99] Heinrich B, Gertz EM, Schäffer AA, et al. The tumour microenvironment shapes innate lymphoid cells in patients with hepatocellular carcinoma. Gut. 2022; 71(6): 1161-1175.

[100] Xu X, Ye L, Zhang Q, et al. Group-2 innate lymphoid cells promote HCC progression through CXCL2-neutrophil-induced immunosuppression. Hepatology. 2021; 74(5): 2526-2543.

[101] Liu N, Chang CW, Steer CJ, Wang XW, Song G. MicroRNA-15a/16-1 prevents hepatocellular carcinoma by disrupting the communication between Kupffer cells and regulatory T cells. Gastroenterology. 2022; 162(2): 575-589.

[102] Liu N, Wang X, Steer CJ, Song G. MicroRNA-206 promotes the recruitment of CD8(+) T cells by driving M1 polarisation of Kupffer cells. Gut. 2022; 71(8): 1642-1655.

[103] Sun G, Liu H, Zhao J, et al. Macrophage GSK3β-deficiency inhibits the progression of hepatocellular carcinoma and enhances the sensitivity of anti-PD1 immunotherapy. J Immunother Cancer. 2022; 10(12).

[104] Kim JH, Han JW, Choi YJ, et al. Functions of human liver CD69(+)CD103(−)CD8(+) T cells depend on HIF-2α activity in healthy and pathologic livers. J Hepatol. 2020; 72(6): 1170-1181.

[105] Park JS, Ma YQ, Wang F, et al. A3AR antagonism mitigates metabolic dysfunction-associated steatotic liver disease by exploiting monocyte-derived Kupffer cell necroptosis and inflammation resolution. Metabolism. 2025; 164:156114.

[106] Su T, He Y, Wang M, et al. Macrophage-hepatocyte circuits mediated by grancalcin aggravate the progression of metabolic dysfunction associated steatohepatitis. Adv Sci (Weinh). 2024; 11(42):e2406500.

[107] Park JS, Lee J, Wang F, et al. A1AT dysregulation of metabolically stressed hepatocytes by Kupffer cells drives MASH and fibrosis. Exp Mol Med. 2025; 57(2): 450-465.

[108] Zhang J, Wang Y, Fan M, et al. Reactive oxygen species regulation by NCF1 governs ferroptosis susceptibility of Kupffer cells to MASH. Cell Metab. 2024; 36(8): 1745-1763.e6.

[109] Park J, Rah SY, An HS, et al. Metformin-induced TTP mediates communication between Kupffer cells and hepatocytes to alleviate hepatic steatosis by regulating lipophagy and necroptosis. Metabolism. 2023; 141:155516.

[110] Lee J, Woo H, Kang H, Park YK, Lee JY. Nicotinamide riboside targets mitochondrial unfolded protein response to reduce alcohol-induced damage in Kupffer cells. J Pathol. 2025; 265(1): 110-122.

[111] Gao H, Jin Z, Bandyopadhyay G, et al. MiR-690 treatment causes decreased fibrosis and steatosis and restores specific Kupffer cell functions in NASH. Cell Metab. 2022; 34(7): 978-990.e4.

[112] Song K, Kwon H, Han C, et al. Yes-associated protein in Kupffer cells enhances the production of proinflammatory cytokines and promotes the development of nonalcoholic steatohepatitis. Hepatology. 2020; 72(1): 72-87.

[113] Ma C, Han M, Heinrich B, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018; 360(6391).

[114] Xu Y, Xiang Z, Alnaggar M, et al. Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer. Cell Mol Immunol. 2021; 18(2): 427-439.

[115] Makkouk A, Yang XC, Barca T, et al. Off-the-shelf Vδ1 gamma delta T cells engineered with glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust antitumor efficacy against hepatocellular carcinoma. J Immunother Cancer. 2021; 9(12).

[116] Chua YC, Draper SL, Le S, et al. Mechanistic insight into the induction of liver tissue-resident memory CD8(+) T cells by glycolipid-peptide vaccination. Cell Rep. 2025; 44(2):115295.

RIGHTS & PERMISSIONS

2026 The Author(s). Precision Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital.