Cancer stem cell-immune cell crosstalk in the tumor microenvironment for liver cancer progression

Abstract

Crosstalk between cancer cells and the immune microenvironment is determinant for liver cancer progression. A tumor subpopulation called liver cancer stem cells (CSCs) significantly accounts for the initiation, metastasis, therapeutic resistance, and recurrence of liver cancer. Emerging evidence demonstrates that the interaction between liver CSCs and immune cells plays a crucial role in shaping an immunosuppressive microenvironment and determining immunotherapy responses. This review sheds light on the bidirectional crosstalk between liver CSCs and immune cells for liver cancer progression, as well as the underlying molecular mechanisms after presenting an overview of liver CSCs characteristic and their microenvironment. Finally, we discuss the potential application of liver CSCs-targeted immunotherapy for liver cancer treatment.

Keywords

liver cancer / cancer stem cell / immune cell / immunotherapy

References

[1] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71(3): 209–249

[2] Huang A, Yang XR, Chung WY, Dennison AR, Zhou J. Targeted therapy for hepatocellular carcinoma. Signal Transduct Target Ther 2020; 5(1): 146

[3] Jörs S, Jeliazkova P, Ringelhan M, Thalhammer J, Dürl S, Ferrer J, Sander M, Heikenwalder M, Schmid RM, Siveke JT, Geisler F. Lineage fate of ductular reactions in liver injury and carcinogenesis. J Clin Invest 2015; 125(6): 2445–2457

[4] Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003; 37(2): 429–442

[5] Oishi N, Yamashita T, Kaneko S. Molecular biology of liver cancer stem cells. Liver Cancer 2014; 3(2): 71–84

[6] Joo I, Kim H, Lee JM. Cancer stem cells in primary liver cancers: pathological concepts and imaging findings. Korean J Radiol 2015; 16(1): 50–68

[7] Hinshaw DC, Shevde LA. The tumor microenvironment innately modulates cancer progression. Cancer Res 2019; 79(18): 4557–4566

[8] Dong KS, Chen Y, Yang G, Liao ZB, Zhang HW, Liang HF, Chen XP, Dong HH. TGF-β1 accelerates the hepatitis B virus X-induced malignant transformation of hepatic progenitor cells by upregulating miR-199a-3p. Oncogene 2020; 39(8): 1807–1820

[9] Bayik D, Lathia JD. Cancer stem cell-immune cell crosstalk in tumour progression. Nat Rev Cancer 2021; 21(8): 526–536

[10] He G, Dhar D, Nakagawa H, Font-Burgada J, Ogata H, Jiang Y, Shalapour S, Seki E, Yost SE, Jepsen K, Frazer KA, Harismendy O, Hatziapostolou M, Iliopoulos D, Suetsugu A, Hoffman RM, Tateishi R, Koike K, Karin M. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell 2013; 155(2): 384–396

[11] Wu K, Ding J, Chen C, Sun W, Ning BF, Wen W, Huang L, Han T, Yang W, Wang C, Li Z, Wu MC, Feng GS, Xie WF, Wang HY. Hepatic transforming growth factor beta gives rise to tumor-initiating cells and promotes liver cancer development. Hepatology 2012; 56(6): 2255–2267

[12] Tang Y, Kitisin K, Jogunoori W, Li C, Deng CX, Mueller SC, Ressom HW, Rashid A, He AR, Mendelson JS, Jessup JM, Shetty K, Zasloff M, Mishra B, Reddy EP, Johnson L, Mishra L. Progenitor/stem cells give rise to liver cancer due to aberrant TGF-β and IL-6 signaling. Proc Natl Acad Sci USA 2008; 105(7): 2445–2450

[13] Jing Y, Sun K, Liu W, Sheng D, Zhao S, Gao L, Wei L. Tumor necrosis factor-α promotes hepatocellular carcinogenesis through the activation of hepatic progenitor cells. Cancer Lett 2018; 434: 22–32

[14] Holczbauer Á, Factor VM, Andersen JB, Marquardt JU, Kleiner DE, Raggi C, Kitade M, Seo D, Akita H, Durkin ME, Thorgeirsson SS. Modeling pathogenesis of primary liver cancer in lineage-specific mouse cell types. Gastroenterology 2013; 145(1): 221–231

[15] Mu X, Español-Suñer R, Mederacke I, Affò S, Manco R, Sempoux C, Lemaigre FP, Adili A, Yuan D, Weber A, Unger K, Heikenwälder M, Leclercq IA, Schwabe RF. Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment. J Clin Invest 2015; 125(10): 3891–3903

[16] Huch M, Dollé L. The plastic cellular states of liver cells: are EpCAM and Lgr5 fit for purpose?. Hepatology 2016; 64(2): 652–662

[17] Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO, Brooks M, Reinhardt F, Su Y, Polyak K, Arendt LM, Kuperwasser C, Bierie B, Weinberg RA. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci USA 2011; 108(19): 7950–7955

[18] Fekir K, Dubois-Pot-Schneider H, Désert R, Daniel Y, Glaise D, Rauch C, Morel F, Fromenty B, Musso O, Cabillic F, Corlu A. Retrodifferentiation of human tumor hepatocytes to stem cells leads to metabolic reprogramming and chemoresistance. Cancer Res 2019; 79(8): 1869–1883

[19] Li XF, Chen C, Xiang DM, Qu L, Sun W, Lu XY, Zhou TF, Chen SZ, Ning BF, Cheng Z, Xia MY, Shen WF, Yang W, Wen W, Lee TKW, Cong WM, Wang HY, Ding J. Chronic inflammation-elicited liver progenitor cell conversion to liver cancer stem cell with clinical significance. Hepatology 2017; 66(6): 1934–1951

[20] Matsumoto T, Takai A, Eso Y, Kinoshita K, Manabe T, Seno H, Chiba T, Marusawa H. Proliferating EpCAM-positive ductal cells in the inflamed liver give rise to hepatocellular carcinoma. Cancer Res 2017; 77(22): 6131–6143

[21] Ang CH, Hsu SH, Guo F, Tan CT, Yu VC, Visvader JE, Chow PKH, Fu NY. Lgr5⁺ pericentral hepatocytes are self-maintained in normal liver regeneration and susceptible to hepatocarcinogenesis. Proc Natl Acad Sci USA 2019; 116(39): 19530–19540

[22] Tsui YM, Chan LK, Ng IO. Cancer stemness in hepatocellular carcinoma: mechanisms and translational potential. Br J Cancer 2020; 122(10): 1428–1440

[23] Lee TK, Guan XY, Ma S. Cancer stem cells in hepatocellular carcinoma — from origin to clinical implications. Nat Rev Gastroenterol Hepatol 2022; 19(1): 26–44

[24] Mishra L, Banker T, Murray J, Byers S, Thenappan A, He AR, Shetty K, Johnson L, Reddy EP. Liver stem cells and hepatocellular carcinoma. Hepatology 2009; 49(1): 318–329

[25] Jang JW, Song Y, Kim SH, Kim JS, Kim KM, Choi EK, Kim J, Seo HR. CD133 confers cancer stem-like cell properties by stabilizing EGFR-AKT signaling in hepatocellular carcinoma. Cancer Lett 2017; 389: 1–10

[26] Yang ZF, Ho DW, Ng MN, Lau CK, Yu WC, Ngai P, Chu PWK, Lam CT, Poon RTP, Fan ST. Significance of CD90⁺ cancer stem cells in human liver cancer. Cancer Cell 2008; 13(2): 153–166

[27] Mima K, Okabe H, Ishimoto T, Hayashi H, Nakagawa S, Kuroki H, Watanabe M, Beppu T, Tamada M, Nagano O, Saya H, Baba H. CD44s regulates the TGF-β-mediated mesenchymal phenotype and is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Res 2012; 72(13): 3414–3423

[28] Yamashita T, Forgues M, Wang W, Kim JW, Ye Q, Jia H, Budhu A, Zanetti KA, Chen Y, Qin LX, Tang ZY, Wang XW. EpCAM and α-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma. Cancer Res 2008; 68(5): 1451–1461

[29] Haraguchi N, Ishii H, Mimori K, Tanaka F, Ohkuma M, Kim HM, Akita H, Takiuchi D, Hatano H, Nagano H, Barnard GF, Doki Y, Mori M. CD13 is a therapeutic target in human liver cancer stem cells. J Clin Invest 2010; 120(9): 3326–3339

[30] Lee TKW, Cheung VCH, Lu P, Lau EYT, Ma S, Tang KH, Tong M, Lo J, Ng IOL. Blockade of CD47-mediated cathepsin S/protease-activated receptor 2 signaling provides a therapeutic target for hepatocellular carcinoma. Hepatology 2014; 60(1): 179–191

[31] Xu X, Liu RF, Zhang X, Huang LY, Chen F, Fei QL, Han ZG. DLK1 as a potential target against cancer stem/progenitor cells of hepatocellular carcinoma. Mol Cancer Ther 2012; 11(3): 629–638

[32] Liu S, Li N, Yu X, Xiao X, Cheng K, Hu J, Wang J, Zhang D, Cheng S, Liu S. Expression of intercellular adhesion molecule 1 by hepatocellular carcinoma stem cells and circulating tumor cells. Gastroenterology 2013; 144(5): 1031–1041.e10

[33] Zhao W, Wang L, Han H, Jin K, Lin N, Guo T, Chen Y, Cheng H, Lu F, Fang W, Wang Y, Xing B, Zhang Z. 1B50-1, a mAb raised against recurrent tumor cells, targets liver tumor-initiating cells by binding to the calcium channel α2δ1 subunit. Cancer Cell 2013; 23(4): 541–556

[34] Kawai T, Yasuchika K, Ishii T, Katayama H, Yoshitoshi EY, Ogiso S, Kita S, Yasuda K, Fukumitsu K, Mizumoto M, Hatano E, Uemoto S. Keratin 19, a cancer stem cell marker in human hepatocellular carcinoma. Clin Cancer Res 2015; 21(13): 3081–3091

[35] Tang KH, Ma S, Lee TK, Chan YP, Kwan PS, Tong CM, Ng IO, Man K, To KF, Lai PB, Lo CM, Guan XY, Chan KW. CD133⁺ liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling. Hepatology 2012; 55(3): 807–820

[36] Hur W, Ryu JY, Kim HU, Hong SW, Lee EB, Lee SY, Yoon SK. Systems approach to characterize the metabolism of liver cancer stem cells expressing CD133. Sci Rep 2017; 7(1): 45557

[37] Yang ZF, Ngai P, Ho DW, Yu WC, Ng MNP, Lau CK, Li MLY, Tam KH, Lam CT, Poon RTP, Fan ST. Identification of local and circulating cancer stem cells in human liver cancer. Hepatology 2008; 47(3): 919–928

[38] Ishimoto T, Nagano O, Yae T, Tamada M, Motohara T, Oshima H, Oshima M, Ikeda T, Asaba R, Yagi H, Masuko T, Shimizu T, Ishikawa T, Kai K, Takahashi E, Imamura Y, Baba Y, Ohmura M, Suematsu M, Baba H, Saya H. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc^- and thereby promotes tumor growth. Cancer Cell 2011; 19(3): 387–400

[39] Kim JW, Ye Q, Forgues M, Chen Y, Budhu A, Sime J, Hofseth LJ, Kaul R, Wang XW. Cancer-associated molecular signature in the tissue samples of patients with cirrhosis. Hepatology 2004; 39(2): 518–527

[40] Kawai T, Yasuchika K, Seo S, Higashi T, Ishii T, Miyauchi Y, Kojima H, Yamaoka R, Katayama H, Yoshitoshi EY, Ogiso S, Kita S, Yasuda K, Fukumitsu K, Nakamoto Y, Hatano E, Uemoto S. Identification of keratin 19-positive cancer stem cells associating human hepatocellular carcinoma using ¹⁸F-fluorodeoxyglucose positron emission tomography. Clin Cancer Res 2017; 23(6): 1450–1460

[41] Wang N, Li MY, Liu Y, Yu J, Ren J, Zheng Z, Wang S, Yang S, Yang SL, Liu LP, Hu BG, Chong CC, Merchant JL, Lai PB, Chen GG. ZBP-89 negatively regulates self-renewal of liver cancer stem cells via suppression of Notch1 signaling pathway. Cancer Lett 2020; 472: 70–80

[42] Wang N, Wang S, Yang SL, Liu LP, Li MY, Lai PBS, Chen GG. Targeting ZBP-89 for the treatment of hepatocellular carcinoma. Expert Opin Ther Targets 2018; 22(10): 817–822

[43] Nio K, Yamashita T, Kaneko S. The evolving concept of liver cancer stem cells. Mol Cancer 2017; 16(1): 4

[44] Monga SPS. Role of Wnt/β-catenin signaling in liver metabolism and cancer. Int J Biochem Cell Biol 2011; 43(7): 1021–1029

[45] Chang PH, Sekine K, Chao HM, Hsu SH, Chern E. Chitosan promotes cancer progression and stem cell properties in association with Wnt signaling in colon and hepatocellular carcinoma cells. Sci Rep 2017; 8(1): 45751

[46] Fan Z, Duan J, Wang L, Xiao S, Li L, Yan X, Yao W, Wu L, Zhang S, Zhang Y, Li Y, Zhu X, Hu Y, Zhang D, Jiao S, Xu X. PTK2 promotes cancer stem cell traits in hepatocellular carcinoma by activating Wnt/β-catenin signaling. Cancer Lett 2019; 450: 132–143

[47] Ram Makena M, Gatla H, Verlekar D, Sukhavasi SK, Pandey MC, Pramanik K. Wnt/β-catenin signaling: the culprit in pancreatic carcinogenesis and therapeutic resistance. Int J Mol Sci 2019; 20(17): 4242

[48] Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, Jia H, Ye Q, Qin LX, Wauthier E, Reid LM, Minato H, Honda M, Kaneko S, Tang ZY, Wang XW. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology 2009; 136(3): 1012–1024

[49] Ma S, Chan KW, Hu L, Lee TK, Wo JY, Ng IO, Zheng BJ, Guan XY. Identification and characterization of tumorigenic liver cancer stem/progenitor cells. Gastroenterology 2007; 132(7): 2542–2556

[50] Zhu J, Yu H, Chen S, Yang P, Dong Z, Ling Y, Tang H, Bai S, Yang W, Tang L, Shen F, Wang H, Wen W. Prognostic significance of combining high mobility group Box-1 and OV-6 expression in hepatocellular carcinoma. Sci China Life Sci 2018; 61(8): 912–923

[51] Mokkapati S, Niopek K, Huang L, Cunniff KJ, Ruteshouser EC, deCaestecker M, Finegold MJ, Huff V. β-catenin activation in a novel liver progenitor cell type is sufficient to cause hepatocellular carcinoma and hepatoblastoma. Cancer Res 2014; 74(16): 4515–4525

[52] Xiang D, Cheng Z, Liu H, Wang X, Han T, Sun W, Li X, Yang W, Chen C, Xia M, Liu N, Yin S, Jin G, Lee T, Dong L, Hu H, Wang H, Ding J. Shp2 promotes liver cancer stem cell expansion by augmenting β-catenin signaling and predicts chemotherapeutic response of patients. Hepatology 2017; 65(5): 1566–1580

[53] Leung HW, Leung CON, Lau EY, Chung KPS, Mok EH, Lei MML, Leung RWH, Tong M, Keng VW, Ma C, Zhao Q, Ng IOL, Ma S, Lee TK. EPHB2 activates β-catenin to enhance cancer stem cell properties and drive sorafenib resistance in hepatocellular carcinoma. Cancer Res 2021; 81(12): 3229–3240

[54] Yamashita T, Budhu A, Forgues M, Wang XW. Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma. Cancer Res 2007; 67(22): 10831–10839

[55] Kahraman DC, Kahraman T, Cetin-Atalay R. Targeting PI3K/Akt/mTOR pathway identifies differential expression and functional role of IL8 in liver cancer stem cell enrichment. Mol Cancer Ther 2019; 18(11): 2146–2157

[56] Wang XQ, Zhang W, Lui ELH, Zhu Y, Lu P, Yu X, Sun J, Yang S, Poon RTP, Fan ST. Notch1-Snail1-E-cadherin pathway in metastatic hepatocellular carcinoma. Int J Cancer 2012; 131(3): E163–E172

[57] Xiao S, Chang RM, Yang MY, Lei X, Liu X, Gao WB, Xiao JL, Yang LY. Actin-like 6A predicts poor prognosis of hepatocellular carcinoma and promotes metastasis and epithelial-mesenchymal transition. Hepatology 2016; 63(4): 1256–1271

[58] Zhu P, Wang Y, Du Y, He L, Huang G, Zhang G, Yan X, Fan Z. C8orf4 negatively regulates self-renewal of liver cancer stem cells via suppression of NOTCH2 signalling. Nat Commun 2015; 6(1): 7122

[59] Wang R, Li Y, Tsung A, Huang H, Du Q, Yang M, Deng M, Xiong S, Wang X, Zhang L, Geller DA, Cheng B, Billiar TR. iNOS promotes CD24⁺CD133⁺ liver cancer stem cell phenotype through a TACE/ADAM17-dependent Notch signaling pathway. Proc Natl Acad Sci USA 2018; 115(43): E10127–E10136

[60] Lin L, Amin R, Gallicano GI, Glasgow E, Jogunoori W, Jessup JM, Zasloff M, Marshall JL, Shetty K, Johnson L, Mishra L, He AR. The STAT3 inhibitor NSC 74859 is effective in hepatocellular cancers with disrupted TGF-β signaling. Oncogene 2009; 28(7): 961–972

[61] Wang C, Yang W, Yan HX, Luo T, Zhang J, Tang L, Wu FQ, Zhang HL, Yu LX, Zheng LY, Li YQ, Dong W, He YQ, Liu Q, Zou SS, Lin Y, Hu L, Li Z, Wu MC, Wang HY. Hepatitis B virus X (HBx) induces tumorigenicity of hepatic progenitor cells in 3,5-diethoxycarbonyl-1,4-dihydrocollidine-treated HBx transgenic mice. Hepatology 2012; 55(1): 108–120

[62] Lee TK, Castilho A, Cheung VC, Tang KH, Ma S, Ng IO. CD24⁺ liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell 2011; 9(1): 50–63

[63] Xie C, Zhu J, Wang X, Chen J, Geng S, Wu J, Zhong C, Li X. Tobacco smoke induced hepatic cancer stem cell-like properties through IL-33/p38 pathway. J Exp Clin Cancer Res 2019; 38(1): 39

[64] Toh TB, Lim JJ, Hooi L, Rashid MBMA, Chow EK. Targeting Jak/Stat pathway as a therapeutic strategy against SP/CD44⁺ tumorigenic cells in Akt/β-catenin-driven hepatocellular carcinoma. J Hepatol 2020; 72(1): 104–118

[65] Schiavoni G, Gabriele L, Mattei F. The tumor microenvironment: a pitch for multiple players. Front Oncol 2013; 3: 90

[66] Fang T, Lv H, Lv G, Li T, Wang C, Han Q, Yu L, Su B, Guo L, Huang S, Cao D, Tang L, Tang S, Wu M, Yang W, Wang H. Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun 2018; 9(1): 191

[67] Tian B, Luo Q, Ju Y, Song G. A soft matrix enhances the cancer stem cell phenotype of HCC cells. Int J Mol Sci 2019; 20(11): 2831

[68] Loong JH, Wong TL, Tong M, Sharma R, Zhou L, Ng KY, Yu HJ, Li CH, Man K, Lo CM, Guan XY, Lee TK, Yun JP, Ma SK. Glucose deprivation-induced aberrant FUT1-mediated fucosylation drives cancer stemness in hepatocellular carcinoma. J Clin Invest 2021; 131(11): e143377

[69] Liu Z, Dai X, Wang T, Zhang C, Zhang W, Zhang W, Zhang Q, Wu K, Liu F, Liu Y, Wu J. Hepatitis B virus PreS1 facilitates hepatocellular carcinoma development by promoting appearance and self-renewal of liver cancer stem cells. Cancer Lett 2017; 400: 149–160

[70] Ding WB, Wang MC, Yu J, Huang G, Sun DP, Liu L, Zhang JN, Yang Y, Liu H, Zhou WP, Yang F, Yuan SX. HBV/pregenomic RNA increases the stemness and promotes the development of HBV-related HCC through reciprocal regulation with insulin-like growth factor 2 mRNA-binding protein 3. Hepatology 2021; 74(3): 1480–1495

[71] Lau EYT, Lo J, Cheng BYL, Ma MKF, Lee JMF, Ng JKY, Chai S, Lin CH, Tsang SY, Ma S, Ng IOL, Lee TKW. Cancer-associated fibroblasts regulate tumor-initiating cell plasticity in hepatocellular carcinoma through c-Met/FRA1/HEY1 signaling. Cell Rep 2016; 15(6): 1175–1189

[72] Liu C, Liu L, Chen X, Cheng J, Zhang H, Zhang C, Shan J, Shen J, Qian C. LSD1 stimulates cancer-associated fibroblasts to drive notch3-dependent self-renewal of liver cancer stem-like cells. Cancer Res 2018; 78(4): 938–949

[73] Xiong S, Wang R, Chen Q, Luo J, Wang J, Zhao Z, Li Y, Wang Y, Wang X, Cheng B. Cancer-associated fibroblasts promote stem cell-like properties of hepatocellular carcinoma cells through IL-6/STAT3/Notch signaling. Am J Cancer Res 2018; 8(2): 302–316

[74] Tavora B, Mederer T, Wessel KJ, Ruffing S, Sadjadi M, Missmahl M, Ostendorf BN, Liu X, Kim JY, Olsen O, Welm AL, Goodarzi H, Tavazoie SF. Tumoural activation of TLR3-SLIT2 axis in endothelium drives metastasis. Nature 2020; 586(7828): 299–304

[75] Conigliaro A, Costa V, Lo Dico A, Saieva L, Buccheri S, Dieli F, Manno M, Raccosta S, Mancone C, Tripodi M, De Leo G, Alessandro R. CD90⁺ liver cancer cells modulate endothelial cell phenotype through the release of exosomes containing H19 lncRNA. Mol Cancer 2015; 14(1): 155

[76] Yao H, Liu N, Lin MC, Zheng J. Positive feedback loop between cancer stem cells and angiogenesis in hepatocellular carcinoma. Cancer Lett 2016; 379(2): 213–219

[77] Bishayee A. The role of inflammation and liver cancer. Adv Exp Med Biol 2014; 816: 401–435

[78] Wan S, Zhao E, Kryczek I, Vatan L, Sadovskaya A, Ludema G, Simeone DM, Zou W, Welling TH. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 2014; 147(6): 1393–1404

[79] Chen Y, Wen H, Zhou C, Su Q, Lin Y, Xie Y, Huang Y, Qiu Q, Lin J, Huang X, Tan W, Min C, Wang C. TNF-α derived from M2 tumor-associated macrophages promotes epithelial-mesenchymal transition and cancer stemness through the Wnt/β-catenin pathway in SMMC-7721 hepatocellular carcinoma cells. Exp Cell Res 2019; 378(1): 41–50

[80] Fan QM, Jing YY, Yu GF, Kou XR, Ye F, Gao L, Li R, Zhao QD, Yang Y, Lu ZH, Wei LX. Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer Lett 2014; 352(2): 160–168

[81] Liu YC, Yeh CT, Lin KH. Cancer stem cell functions in hepatocellular carcinoma and comprehensive therapeutic strategies. Cells 2020; 9(6): 1331

[82] Chen J, Zheng DX, Yu XJ, Sun HW, Xu YT, Zhang YJ, Xu J. Macrophages induce CD47 upregulation via IL-6 and correlate with poor survival in hepatocellular carcinoma patients. OncoImmunology 2019; 8(11): e1652540

[83] Ye LY, Chen W, Bai XL, Xu XY, Zhang Q, Xia XF, Sun X, Li GG, Hu QD, Fu QH, Liang TB. Hypoxia-induced epithelial-to-mesenchymal transition in hepatocellular carcinoma induces an immunosuppressive tumor microenvironment to promote metastasis. Cancer Res 2016; 76(4): 818–830

[84] Zhou SL, Yin D, Hu ZQ, Luo CB, Zhou ZJ, Xin HY, Yang XR, Shi YH, Wang Z, Huang XW, Cao Y, Fan J, Zhou J. A positive feedback loop between cancer stem-like cells and tumor-associated neutrophils controls hepatocellular carcinoma progression. Hepatology 2019; 70(4): 1214–1230

[85] Schramm C, Oo YH, Lohse AW. Tolerance and autoimmunity in the liver. Semin Immunopathol 2022; 44(4): 393–395

[86] Chaudhary B, Elkord E. Regulatory T cells in the tumor microenvironment and cancer progression: role and therapeutic targeting. Vaccines (Basel) 2016; 4(3): 28

[87] Shi C, Chen Y, Chen Y, Yang Y, Bing W, Qi J. CD4⁺ CD25⁺ regulatory T cells promote hepatocellular carcinoma invasion via TGF-β1-induced epithelial-mesenchymal transition. OncoTargets Ther 2018; 12: 279–289

[88] Rahma OE, Hodi FS. The intersection between tumor angiogenesis and immune suppression. Clin Cancer Res 2019; 25(18): 5449–5457

[89] Yang T, Zhang W, Wang L, Xiao C, Wang L, Gong Y, Huang D, Guo B, Li Q, Xiang Y, Nan Y. Co-culture of dendritic cells and cytokine-induced killer cells effectively suppresses liver cancer stem cell growth by inhibiting pathways in the immune system. BMC Cancer 2018; 18(1): 984

[90] Wang G, Xu J, Zhao J, Yin W, Liu D, Chen W, Hou SX. Arf1-mediated lipid metabolism sustains cancer cells and its ablation induces anti-tumor immune responses in mice. Nat Commun 2020; 11(1): 220

[91] Zhong M, Zhong C, Cui W, Wang G, Zheng G, Li L, Zhang J, Ren R, Gao H, Wang T, Li X, Che J, Gohda E. Induction of tolerogenic dendritic cells by activated TGF-β/Akt/Smad2 signaling in RIG-I-deficient stemness-high human liver cancer cells. BMC Cancer 2019; 19(1): 439

[92] Pardee AD, Shi J, Butterfield LH. Tumor-derived α-fetoprotein impairs the differentiation and T cell stimulatory activity of human dendritic cells. J Immunol 2014; 193(11): 5723–5732

[93] Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001; 410(6832): 1107–1111

[94] Lv H, Lv G, Chen C, Zong Q, Jiang G, Ye D, Cui X, He Y, Xiang W, Han Q, Tang L, Yang W, Wang H. NAD⁺ metabolism maintains inducible PD-L1 expression to drive tumor immune evasion. Cell Metab 2021; 33(1): 110–127.e5

[95] Dai X, Guo Y, Hu Y, Bao X, Zhu X, Fu Q, Zhang H, Tong Z, Liu L, Zheng Y, Zhao P, Fang W. Immunotherapy for targeting cancer stem cells in hepatocellular carcinoma. Theranostics 2021; 11(7): 3489–3501

[96] Hsu JM, Xia W, Hsu YH, Chan LC, Yu WH, Cha JH, Chen CT, Liao HW, Kuo CW, Khoo KH, Hsu JL, Li CW, Lim SO, Chang SS, Chen YC, Ren GX, Hung MC. STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion. Nat Commun 2018; 9(1): 1908

[97] Morrison BJ, Steel JC, Morris JC. Reduction of MHC-I expression limits T-lymphocyte-mediated killing of cancer-initiating cells. BMC Cancer 2018; 18(1): 469

[98] Dianat-Moghadam H, Rokni M, Marofi F, Panahi Y, Yousefi M. Natural killer cell-based immunotherapy: from transplantation toward targeting cancer stem cells. J Cell Physiol 2018; 234(1): 259–273

[99] Cheung PF, Yip CW, Wong NC, Fong DY, Ng LW, Wan AM, Wong CK, Cheung TT, Ng IO, Poon RT, Fan ST, Cheung ST. Granulin-epithelin precursor renders hepatocellular carcinoma cells resistant to natural killer cytotoxicity. Cancer Immunol Res 2014; 2(12): 1209–1219

[100] Lam KH, Ma S. Noncellular components in the liver cancer stem cell niche: biology and potential clinical implications. Hepatology 2023; 78(3): 991–1005

[101] You Y, Zheng Q, Dong Y, Xie X, Wang Y, Wu S, Zhang L, Wang Y, Xue T, Wang Z, Chen R, Wang Y, Cui J, Ren Z. Matrix stiffness-mediated effects on stemness characteristics occurring in HCC cells. Oncotarget 2016; 7(22): 32221–32231

[102] Kohga K, Tatsumi T, Takehara T, Tsunematsu H, Shimizu S, Yamamoto M, Sasakawa A, Miyagi T, Hayashi N. Expression of CD133 confers malignant potential by regulating metalloproteinases in human hepatocellular carcinoma. J Hepatol 2010; 52(6): 872–879

[103] Zhao W, Lv M, Yang X, Zhou J, Xing B, Zhang Z. Liver tumor-initiating cells initiate the formation of a stiff cancer stem cell microenvironment niche by secreting LOX. Carcinogenesis 2022; 43(8): 766–778

[104] Cui CP, Wong CC, Kai AK, Ho DW, Lau EY, Tsui YM, Chan LK, Cheung TT, Chok KS, Chan ACY, Lo RC, Lee JM, Lee TK, Ng IOL. SENP1 promotes hypoxia-induced cancer stemness by HIF-1α deSUMOylation and SENP1/HIF-1α positive feedback loop. Gut 2017; 66(12): 2149–2159

[105] Liu G, Luo Q, Li H, Liu Q, Ju Y, Song G. Increased oxidative phosphorylation is required for stemness maintenance in liver cancer stem cells from hepatocellular carcinoma cell line HCCLM3 cells. Int J Mol Sci 2020; 21(15): 5276

[106] Liu Y, Ren H, Zhou Y, Shang L, Zhang Y, Yang F, Shi X. The hypoxia conditioned mesenchymal stem cells promote hepatocellular carcinoma progression through YAP mediated lipogenesis reprogramming. J Exp Clin Cancer Res 2019; 38(1): 228

[107] Ling S, Shan Q, Zhan Q, Ye Q, Liu P, Xu S, He X, Ma J, Xiang J, Jiang G, Wen X, Feng Z, Wu Y, Feng T, Xu L, Chen K, Zhang X, Wei R, Zhang C, Cen B, Xie H, Song P, Liu J, Zheng S, Xu X. USP22 promotes hypoxia-induced hepatocellular carcinoma stemness by a HIF1α/USP22 positive feedback loop upon TP53 inactivation. Gut 2020; 69(7): 1322–1334

[108] Chisari A, Golán I, Campisano S, Gélabert C, Moustakas A, Sancho P, Caja L. Glucose and amino acid metabolic dependencies linked to stemness and metastasis in different aggressive cancer types. Front Pharmacol 2021; 12: 723798

[109] Lin SH, Liu T, Ming X, Tang Z, Fu L, Schmitt-Kopplin P, Kanawati B, Guan XY, Cai Z. Regulatory role of hexosamine biosynthetic pathway on hepatic cancer stem cell marker CD133 under low glucose conditions. Sci Rep 2016; 6(1): 21184

[110] Fan H, Zhang H, Pascuzzi PE, Andrisani O. Hepatitis B virus X protein induces EpCAM expression via active DNA demethylation directed by RelA in complex with EZH2 and TET2. Oncogene 2016; 35(6): 715–726

[111] Ali N, Allam H, May R, Sureban SM, Bronze MS, Bader T, Umar S, Anant S, Houchen CW. Hepatitis C virus-induced cancer stem cell-like signatures in cell culture and murine tumor xenografts. J Virol 2011; 85(23): 12292–12303

[112] Zhu M, Li W, Lu Y, Dong X, Lin B, Chen Y, Zhang X, Guo J, Li M. HBx drives alpha fetoprotein expression to promote initiation of liver cancer stem cells through activating PI3K/AKT signal pathway. Int J Cancer 2017; 140(6): 1346–1355

[113] Shrivastava S, Mukherjee A, Ray R, Ray RB. Hepatitis C virus induces interleukin-1β (IL-1β)/IL-18 in circulatory and resident liver macrophages. J Virol 2013; 87(22): 12284–12290

[114] Lin X, Zuo S, Luo R, Li Y, Yu G, Zou Y, Zhou Y, Liu Z, Liu Y, Hu Y, Xie Y, Fang W, Liu Z. HBX-induced miR-5188 impairs FOXO1 to stimulate β-catenin nuclear translocation and promotes tumor stemness in hepatocellular carcinoma. Theranostics 2019; 9(25): 7583–7598

[115] Uthaya Kumar DB, Chen CL, Liu JC, Feldman DE, Sher LS, French S, DiNorcia J, French SW, Naini BV, Junrungsee S, Agopian VG, Zarrinpar A, Machida K. TLR4 signaling via NANOG cooperates with STAT3 to activate twist1 and promote formation of tumor-initiating stem-like cells in livers of mice. Gastroenterology 2016; 150(3): 707–719

[116] Fan H, Cui Z, Zhang H, Mani SK, Diab A, Lefrancois L, Fares N, Merle P, Andrisani O. DNA demethylation induces SALL4 gene re-expression in subgroups of hepatocellular carcinoma associated with Hepatitis B or C virus infection. Oncogene 2017; 36(17): 2435–2445

[117] Broz ML, Krummel MF. The emerging understanding of myeloid cells as partners and targets in tumor rejection. Cancer Immunol Res 2015; 3(4): 313–319

[118] Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 2012; 12(4): 253–268

[119] Engblom C, Pfirschke C, Pittet MJ. The role of myeloid cells in cancer therapies. Nat Rev Cancer 2016; 16(7): 447–462

[120] Gentek R, Molawi K, Sieweke MH. Tissue macrophage identity and self-renewal. Immunol Rev 2014; 262(1): 56–73

[121] Wu K, Lin K, Li X, Yuan X, Xu P, Ni P, Xu D. Redefining tumor-associated macrophage subpopulations and functions in the tumor microenvironment. Front Immunol 2020; 11: 1731

[122] Jhunjhunwala S, Hammer C, Delamarre L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. Nat Rev Cancer 2021; 21(5): 298–312

[123] Xiao P, Long X, Zhang L, Ye Y, Guo J, Liu P, Zhang R, Ning J, Yu W, Wei F, Yu J. Neurotensin/IL-8 pathway orchestrates local inflammatory response and tumor invasion by inducing M2 polarization of tumor-associated macrophages and epithelial-mesenchymal transition of hepatocellular carcinoma cells. OncoImmunology 2018; 7(7): e1440166

[124] Zhu F, Li X, Chen S, Zeng Q, Zhao Y, Luo F. Tumor-associated macrophage or chemokine ligand CCL17 positively regulates the tumorigenesis of hepatocellular carcinoma. Med Oncol 2016; 33(2): 17

[125] Yan W, Liu X, Ma H, Zhang H, Song X, Gao L, Liang X, Ma C. Tim-3 fosters HCC development by enhancing TGF-β-mediated alternative activation of macrophages. Gut 2015; 64(10): 1593–1604

[126] Fu XT, Dai Z, Song K, Zhang ZJ, Zhou ZJ, Zhou SL, Zhao YM, Xiao YS, Sun QM, Ding ZB, Fan J. Macrophage-secreted IL-8 induces epithelial-mesenchymal transition in hepatocellular carcinoma cells by activating the JAK2/STAT3/Snail pathway. Int J Oncol 2015; 46(2): 587–596

[127] Peng ZP, Jiang ZZ, Guo HF, Zhou MM, Huang YF, Ning WR, Huang JH, Zheng L, Wu Y. Glycolytic activation of monocytes regulates the accumulation and function of neutrophils in human hepatocellular carcinoma. J Hepatol 2020; 73(4): 906–917

[128] Wang Y, Wang B, Xiao S, Li Y, Chen Q. miR-125a/b inhibits tumor-associated macrophages mediated in cancer stem cells of hepatocellular carcinoma by targeting CD90. J Cell Biochem 2019; 120(3): 3046–3055

[129] Iliopoulos D, Hirsch HA, Struhl K. An epigenetic switch involving NF-κB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 2009; 139(4): 693–706

[130] Barkal AA, Brewer RE, Markovic M, Kowarsky M, Barkal SA, Zaro BW, Krishnan V, Hatakeyama J, Dorigo O, Barkal LJ, Weissman IL. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature 2019; 572(7769): 392–396

[131] Arvanitakis K, Mitroulis I, Germanidis G. Tumor-associated neutrophils in hepatocellular carcinoma pathogenesis, prognosis, and therapy. Cancers (Basel) 2021; 13(12): 2899

[132] Song M, He J, Pan QZ, Yang J, Zhao J, Zhang YJ, Huang Y, Tang Y, Wang Q, He J, Gu J, Li Y, Chen S, Zeng J, Zhou ZQ, Yang C, Han Y, Chen H, Xiang T, Weng DS, Xia JC. Cancer-associated fibroblast-mediated cellular crosstalk supports hepatocellular carcinoma progression. Hepatology 2021; 73(5): 1717–1735

[133] Ma T, Renz BW, Ilmer M, Koch D, Yang Y, Werner J, Bazhin AV. Myeloid-derived suppressor cells in solid tumors. Cells 2022; 11(2): 310

[134] Tcyganov E, Mastio J, Chen E, Gabrilovich DI. Plasticity of myeloid-derived suppressor cells in cancer. Curr Opin Immunol 2018; 51: 76–82

[135] Ostrand-Rosenberg S. Myeloid-derived suppressor cells: more mechanisms for inhibiting antitumor immunity. Cancer Immunol Immunother 2010; 59(10): 1593–1600

[136] Xu M, Zhao Z, Song J, Lan X, Lu S, Chen M, Wang Z, Chen W, Fan X, Wu F, Chen L, Tu J, Ji J. Interactions between interleukin-6 and myeloid-derived suppressor cells drive the chemoresistant phenotype of hepatocellular cancer. Exp Cell Res 2017; 351(2): 142–149

[137] Lee WC, Hsu PY, Hsu HY. Stem cell factor produced by tumor cells expands myeloid-derived suppressor cells in mice. Sci Rep 2020; 10(1): 11257

[138] Liu M, Zhou J, Liu X, Feng Y, Yang W, Wu F, Cheung OK, Sun H, Zeng X, Tang W, Mok MTS, Wong J, Yeung PC, Lai PBS, Chen Z, Jin H, Chen J, Chan SL, Chan AWH, To KF, Sung JJY, Chen M, Cheng AS. Targeting monocyte-intrinsic enhancer reprogramming improves immunotherapy efficacy in hepatocellular carcinoma. Gut 2020; 69(2): 365–379

[139] He Q, Liu M, Huang W, Chen X, Zhang B, Zhang T, Wang Y, Liu D, Xie M, Ji X, Sun M, Tian D, Xia L. IL-1β-induced elevation of solute carrier family 7 member 11 promotes hepatocellular carcinoma metastasis through up-regulating programmed death ligand 1 and colony-stimulating factor 1. Hepatology 2021; 74(6): 3174–3193

[140] Lin Y, Cai Q, Chen Y, Shi T, Liu W, Mao L, Deng B, Ying Z, Gao Y, Luo H, Yang X, Huang X, Shi Y, He R. CAFs shape myeloid-derived suppressor cells to promote stemness of intrahepatic cholangiocarcinoma through 5-lipoxygenase. Hepatology 2022; 75(1): 28–42

[141] Wang S, Sun J, Chen K, Ma P, Lei Q, Xing S, Cao Z, Sun S, Yu Z, Liu Y, Li N. Perspectives of tumor-infiltrating lymphocyte treatment in solid tumors. BMC Med 2021; 19(1): 140

[142] Idos GE, Kwok J, Bonthala N, Kysh L, Gruber SB, Qu C. The prognostic implications of tumor infiltrating lymphocytes in colorectal cancer: a systematic review and meta-analysis. Sci Rep 2020; 10(1): 3360

[143] Ren L, Yu Y, Wang L, Zhu Z, Lu R, Yao Z. Hypoxia-induced CCL28 promotes recruitment of regulatory T cells and tumor growth in liver cancer. Oncotarget 2016; 7(46): 75763–75773

[144] Yang P, Li QJ, Feng Y, Zhang Y, Markowitz GJ, Ning S, Deng Y, Zhao J, Jiang S, Yuan Y, Wang HY, Cheng SQ, Xie D, Wang XF. TGF-β-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell 2012; 22(3): 291–303

[145] Kurebayashi Y, Ojima H, Tsujikawa H, Kubota N, Maehara J, Abe Y, Kitago M, Shinoda M, Kitagawa Y, Sakamoto M. Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification. Hepatology 2018; 68(3): 1025–1041

[146] Calderaro J, Rousseau B, Amaddeo G, Mercey M, Charpy C, Costentin C, Luciani A, Zafrani ES, Laurent A, Azoulay D, Lafdil F, Pawlotsky JM. Programmed death ligand 1 expression in hepatocellular carcinoma: relationship with clinical and pathological features. Hepatology 2016; 64(6): 2038–2046

[147] Hsu JM, Xia W, Hsu YH, Chan LC, Yu WH, Cha JH, Chen CT, Liao HW, Kuo CW, Khoo KH, Hsu JL, Li CW, Lim SO, Chang SS, Chen YC, Ren GX, Hung MC. STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion. Nat Commun 2018; 9(1): 1908

[148] Chan LC, Li CW, Xia W, Hsu JM, Lee HH, Cha JH, Wang HL, Yang WH, Yen EY, Chang WC, Zha Z, Lim SO, Lai YJ, Liu C, Liu J, Dong Q, Yang Y, Sun L, Wei Y, Nie L, Hsu JL, Li H, Ye Q, Hassan MM, Amin HM, Kaseb AO, Lin X, Wang SC, Hung MC. IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion. J Clin Invest 2019; 129(8): 3324–3338

[149] Wei Z, Jia J, Heng G, Xu H, Shan J, Wang G, Liu C, Xia J, Zhou H, Wu M, Yang Z, Wang M, Xiong Z, Huang H, Liu L, Qian C. Sirtuin-1/mitochondrial ribosomal protein S5 axis enhances the metabolic flexibility of liver cancer stem cells. Hepatology 2019; 70(4): 1197–1213

[150] Ruiz de Galarreta M, Bresnahan E, Molina-Sánchez P, Lindblad KE, Maier B, Sia D, Puigvehi M, Miguela V, Casanova-Acebes M, Dhainaut M, Villacorta-Martin C, Singhi AD, Moghe A, von Felden J, Tal Grinspan L, Wang S, Kamphorst AO, Monga SP, Brown BD, Villanueva A, Llovet JM, Merad M, Lujambio A. β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov 2019; 9(8): 1124–1141

[151] Zhu GQ, Wang Y, Wang B, Liu WR, Dong SS, Chen EB, Cai JL, Wan JL, Du JX, Song LN, Chen SP, Yu L, Zhou ZJ, Wang Z, Zhou J, Shi YH, Fan J, Dai Z. Targeting HNRNPM inhibits cancer stemness and enhances antitumor immunity in Wnt-activated hepatocellular carcinoma. Cell Mol Gastroenterol Hepatol 2022; 13(5): 1413–1447

[152] Rodríguez MM, Fiore E, Bayo J, Atorrasagasti C, García M, Onorato A, Domínguez L, Malvicini M, Mazzolini G. 4Mu decreases CD47 expression on hepatic cancer stem cells and primes a potent antitumor T cell response induced by interleukin-12. Mol Ther 2018; 26(12): 2738–2750

[153] Cheung ST, Cheung PFY, Cheng CKC, Wong NCL, Fan ST. Granulin-epithelin precursor and ATP-dependent binding cassette (ABC)B5 regulate liver cancer cell chemoresistance. Gastroenterology 2011; 140(1): 344–355

[154] Cheung PF, Yip CW, Wong NC, Fong DY, Ng LW, Wan AM, Wong CK, Cheung TT, Ng IO, Poon RT, Fan ST, Cheung ST. Granulin-epithelin precursor renders hepatocellular carcinoma cells resistant to natural killer cytotoxicity. Cancer Immunol Res 2014; 2(12): 1209–1219

[155] Park DJ, Sung PS, Kim JH, Lee GW, Jang JW, Jung ES, Bae SH, Choi JY, Yoon SK. EpCAM-high liver cancer stem cells resist natural killer cell-mediated cytotoxicity by upregulating CEACAM1. J Immunother Cancer 2020; 8(1): e000301

[156] Zhang PF, Gao C, Huang XY, Lu JC, Guo XJ, Shi GM, Cai JB, Ke AW. Cancer cell-derived exosomal circUHRF1 induces natural killer cell exhaustion and may cause resistance to anti-PD1 therapy in hepatocellular carcinoma. Mol Cancer 2020; 19(1): 110

[157] Ma Y, Shurin GV, Peiyuan Z, Shurin MR. Dendritic cells in the cancer microenvironment. J Cancer 2013; 4(1): 36–44

[158] Ng KY, Chai S, Tong M, Guan XY, Lin CH, Ching YP, Xie D, Cheng AS, Ma S. C-terminal truncated hepatitis B virus X protein promotes hepatocellular carcinogenesis through induction of cancer and stem cell-like properties. Oncotarget 2016; 7(17): 24005–24017

[159] Weiner GJ. Building better monoclonal antibody-based therapeutics. Nat Rev Cancer 2015; 15(6): 361–370

[160] Sun YF, Xu Y, Yang XR, Guo W, Zhang X, Qiu SJ, Shi RY, Hu B, Zhou J, Fan J. Circulating stem cell-like epithelial cell adhesion molecule-positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection. Hepatology 2013; 57(4): 1458–1468

[161] Zhang P, Shi B, Gao H, Jiang H, Kong J, Yan J, Pan X, Li K, Zhang P, Yao M, Yang S, Gu J, Wang H, Li Z. An EpCAM/CD3 bispecific antibody efficiently eliminates hepatocellular carcinoma cells with limited galectin-1 expression. Cancer Immunol Immunother 2014; 63(2): 121–132

[162] Huang J, Li C, Wang Y, Lv H, Guo Y, Dai H, Wicha MS, Chang AE, Li Q. Cytokine-induced killer (CIK) cells bound with anti-CD3/anti-CD133 bispecific antibodies target CD133(high) cancer stem cells in vitro and in vivo. Clin Immunol 2013; 149(1): 156–168

[163] Xiao Z, Chung H, Banan B, Manning PT, Ott KC, Lin S, Capoccia BJ, Subramanian V, Hiebsch RR, Upadhya GA, Mohanakumar T, Frazier WA, Lin Y, Chapman WC. Antibody mediated therapy targeting CD47 inhibits tumor progression of hepatocellular carcinoma. Cancer Lett 2015; 360(2): 302–309

[164] Wang L, Su W, Liu Z, Zhou M, Chen S, Chen Y, Lu D, Liu Y, Fan Y, Zheng Y, Han Z, Kong D, Wu JC, Xiang R, Li Z. CD44 antibody-targeted liposomal nanoparticles for molecular imaging and therapy of hepatocellular carcinoma. Biomaterials 2012; 33(20): 5107–5114

[165] Sun F, Wang T, Jiang J, Wang Y, Ma Z, Li Z, Han Y, Pan M, Cai J, Wang M, Zhang J. Engineering a high-affinity humanized anti-CD24 antibody to target hepatocellular carcinoma by a novel CDR grafting design. Oncotarget 2017; 8(31): 51238–51252

[166] Hirohashi Y, Torigoe T, Inoda S, Takahashi A, Morita R, Nishizawa S, Tamura Y, Suzuki H, Toyota M, Sato N. Immune response against tumor antigens expressed on human cancer stem-like cells/tumor-initiating cells. Immunotherapy 2010; 2(2): 201–211

[167] Saijo H, Hirohashi Y, Torigoe T, Kochin V, Takahashi H, Sato N. Cytotoxic T lymphocytes: the future of cancer stem cell eradication?. Immunotherapy 2013; 5(6): 549–551

[168] Deng Z, Wu Y, Ma W, Zhang S, Zhang YQ. Adoptive T-cell therapy of prostate cancer targeting the cancer stem cell antigen EpCAM. BMC Immunol 2015; 16(1): 1

[169] Alhabbab RY. Targeting cancer stem cells by genetically engineered chimeric antigen receptor T cells. Front Genet 2020; 11: 312

[170] Wang Y, Chen M, Wu Z, Tong C, Dai H, Guo Y, Liu Y, Huang J, Lv H, Luo C, Feng KC, Yang QM, Li XL, Han W. CD133-directed CAR T cells for advanced metastasis malignancies: a phase I trial. OncoImmunology 2018; 7(7): e1440169

[171] Dai H, Tong C, Shi D, Chen M, Guo Y, Chen D, Han X, Wang H, Wang Y, Shen P. Efficacy and biomarker analysis of CD133-directed CAR T cells in advanced hepatocellular carcinoma: a single-arm, open-label, phase II trial. OncoImmunology 2020; 9(1): 1846926

[172] Zhai Y, He K, Huang L, Shang X, Wang G, Yuan G, Han ZG. DLK1-directed chimeric antigen receptor T-cell therapy for hepatocellular carcinoma. Liver Int 2022; 42(11): 2524–2537

[173] Dal Bo M, De Mattia E, Baboci L, Mezzalira S, Cecchin E, Assaraf YG, Toffoli G. New insights into the pharmacological, immunological, and CAR-T-cell approaches in the treatment of hepatocellular carcinoma. Drug Resist Updat 2020; 51: 100702

[174] Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 2010; 18(4): 843–851

[175] Sun S, Hao H, Yang G, Zhang Y, Fu Y. Immunotherapy with CAR-modified T cells: toxicities and overcoming strategies. J Immunol Res 2018; 2018: 2386187

[176] Choi YJ, Park SJ, Park YS, Park HS, Yang KM, Heo K. EpCAM peptide-primed dendritic cell vaccination confers significant anti-tumor immunity in hepatocellular carcinoma cells. PLoS One 2018; 13(1): e0190638

[177] Sun JC, Pan K, Chen MS, Wang QJ, Wang H, Ma HQ, Li YQ, Liang XT, Li JJ, Zhao JJ, Chen YB, Pang XH, Liu WL, Cao Y, Guan XY, Lian QZ, Xia JC. Dendritic cells-mediated CTLs targeting hepatocellular carcinoma stem cells. Cancer Biol Ther 2010; 10(4): 368–375

[178] Pan QZ, Pan K, Wang QJ, Weng DS, Zhao JJ, Zheng HX, Zhang XF, Jiang SS, Lv L, Tang Y, Li YQ, He J, Liu Q, Chen CL, Zhang HX, Xia JC. Annexin A3 as a potential target for immunotherapy of liver cancer stem-like cells. Stem Cells 2015; 33(2): 354–366

[179] Wang Y, Zhao Q, Zhao B, Zheng Y, Zhuang Q, Liao N, Wang P, Cai Z, Zhang D, Zeng Y, Liu X. Remodeling tumor-associated neutrophils to enhance dendritic cell-based HCC neoantigen nano-vaccine efficiency. Adv Sci (Weinh) 2022; 9(11): e2105631

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 82273176, 81902894, 81972779, 81903036, 81622039, 81830054, 91859205, and 81988101), Chinese National Key Project (No. 2018ZX10723204-006-003), Shanghai Municipal Commission of Education Project (No. 201901070007E00065), and Program of Shanghai Academic Research Leader (No. 23XD1404800).

Compliance with ethics guidelines

Yue Ma, Hongwei Lv, Fuxue Xing, Wei Xiang, Zixin Wu, Qiyu Feng, Hongyang Wang, and Wen Yang declare no potential conflicts of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

RIGHTS & PERMISSIONS

2023 Higher Education Press