Intracellular checkpoints for NK cell cancer immunotherapy

Abstract

Natural killer (NK) cells are key innate immune lymphocytes, which play important roles against tumors. However, tumor-infiltrating NK cells are always hypofunctional/exhaustive. On the one hand, this state is contributed by context-dependent interactions between inhibitory NK cell checkpoint receptors and their ligands, which usually vary in different tumor types and stages during tumor development. On the other hand, the inhibitory functions of intracellular checkpoint molecules of NK cells are more similar across different tumor types, representing common mechanisms limiting the potential of NK cell therapy. In this review, representative NK cell intracellular checkpoint molecules in different aspects of NK cell biology were reviewed, and therapeutic potentials were discussed by targeting these molecules to promote antitumor NK cell therapy.

Keywords

genomic editing / NK cell exhaustion / immune checkpoint / inhibitory molecules / immune tolerance

References

[1] Cózar B, Greppi M, Carpentier S, Narni-Mancinelli E, Chiossone L, Vivier E. Tumor-infiltrating natural killer cells. Cancer Discov 2021; 11(1): 34–44

[2] Caligiuri MA. Human natural killer cells. Blood 2008; 112(3): 461–469

[3] Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol 2008; 9(5): 503–510

[4] Coca S, Perez-Piqueras J, Martinez D, Colmenarejo A, Saez MA, Vallejo C, Martos JA, Moreno M. The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer 1997; 79(12): 2320–2328

[5] Peng LS, Zhang JY, Teng YS, Zhao YL, Wang TT, Mao FY, Lv YP, Cheng P, Li WH, Chen N, Duan M, Chen W, Guo G, Zou QM, Zhuang Y. Tumor-associated monocytes/macrophages impair NK-cell function via TGFβ1 in human gastric cancer. Cancer Immunol Res 2017; 5(3): 248–256

[6] Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Xiangming C, Iwashige H, Aridome K, Hokita S, Aikou T. Clinical impact of intratumoral natural killer cell and dendritic cell infiltration in gastric cancer. Cancer Lett 2000; 159(1): 103–108

[7] Jin S, Deng Y, Hao JW, Li Y, Liu B, Yu Y, Shi FD, Zhou QH. NK cell phenotypic modulation in lung cancer environment. PLoS One 2014; 9(10): e109976

[8] Villegas FR, Coca S, Villarrubia VG, Jimenez R, Chillon MJ, Jareno J, Zuil M, Callol L. Prognostic significance of tumor infiltrating natural killer cells subset CD57 in patients with squamous cell lung cancer. Lung Cancer 2002; 35(1): 23–28

[9] Mamessier E, Sylvain A, Thibult ML, Houvenaeghel G, Jacquemier J, Castellano R, Goncalves A, Andre P, Romagne F, Thibault G, Viens P, Birnbaum D, Bertucci F, Moretta A, Olive D. Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. J Clin Invest 2011; 121(9): 3609–3622

[10] Bi J, Tian Z. NK cell exhaustion. Front Immunol 2017; 8: 760

[11] Bi J, Tian Z. NK cell dysfunction and checkpoint immunotherapy. Front Immunol 2019; 10: 1999

[12] Andrews LP, Yano H, Vignali DAA. Inhibitory receptors and ligands beyond PD-1, PD-L1 and CTLA-4: breakthroughs or backups. Nat Immunol 2019; 20(11): 1425–1434

[13] Ravetch JV, Lanier LL. Immune inhibitory receptors. Science 2000; 290(5489): 84–89

[14] Debska-Zielkowska J, Moszkowska G, Zielinski M, Zielinska H, Dukat-Mazurek A, Trzonkowski P, Stefanska K. KIR receptors as key regulators of NK cells activity in health and disease. Cells 2021; 10(7): 1777

[15] Lanier LL. Activating and inhibitory NK cell receptors. Adv Exp Med Biol 1998; 452: 13–18

[16] Lanier LL. NK cell receptors. Annu Rev Immunol 1998; 16(1): 359–393

[17] Lanier LL. Follow the leader: NK cell receptors for classical and nonclassical MHC class I. Cell 1998; 92(6): 705–707

[18] Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. Structure of the human class I histocompatibility antigen, HLA-A2. J Immunol 2005; 174: 6–19

[19] Bjorkman PJ, Saper MA, Samraoui B, Bennett WS, Strominger JL, Wiley DC. Structure of the human class I histocompatibility antigen, HLA-A2. Nature 1987; 329(6139): 506–512

[20] Long EO. Negative signaling by inhibitory receptors: the NK cell paradigm. Immunol Rev 2008; 224(1): 70–84

[21] Takei F, McQueen KL, Maeda M, Wilhelm BT, Lohwasser S, Lian RH, Mager DL. Ly49 and CD94/NKG2: developmentally regulated expression and evolution. Immunol Rev 2001; 181(1): 90–103

[22] Raulet DH, Vance RE, McMahon CW. Regulation of the natural killer cell receptor repertoire. Annu Rev Immunol 2001; 19(1): 291–330

[23] Yokoyama WM, Seaman WE. The Ly-49 and NKR-P1 gene families encoding lectin-like receptors on natural killer cells: the NK gene complex. Annu Rev Immunol 1993; 11(1): 613–635

[24] Brooks AG, Posch PE, Scorzelli CJ, Borrego F, Coligan JE. NKG2A complexed with CD94 defines a novel inhibitory natural killer cell receptor. J Exp Med 1997; 185(4): 795–800

[25] Beldi-Ferchiou A, Lambert M, Dogniaux S, Vely F, Vivier E, Olive D, Dupuy S, Levasseur F, Zucman D, Lebbe C, Sene D, Hivroz C, Caillat-Zucman S. PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma. Oncotarget 2016; 7(45): 72961–72977

[26] Stanietsky N, Simic H, Arapovic J, Toporik A, Levy O, Novik A, Levine Z, Beiman M, Dassa L, Achdout H, Stern-Ginossar N, Tsukerman P, Jonjic S, Mandelboim O. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci USA 2009; 106(42): 17858–17863

[27] Ndhlovu LC, Lopez-Verges S, Barbour JD, Jones RB, Jha AR, Long BR, Schoeffler EC, Fujita T, Nixon DF, Lanier LL. Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity. Blood 2012; 119(16): 3734–3743

[28] Bi J, Jin X, Zheng C, Huang C, Zhong C, Zheng X, Tian Z, Sun H. Checkpoint TIPE2 limits the helper functions of NK cells in supporting antitumor CD8⁺ T cells. Adv Sci (Weinh) 2023; 10(12): 2207499

[29] Cong J, Wang X, Zheng X, Wang D, Fu B, Sun R, Tian Z, Wei H. Dysfunction of natural killer cells by FBP1-induced inhibition of glycolysis during lung cancer progression. Cell Metab 2018; 28(2): 243–255.e5

[30] Delconte RB, Kolesnik TB, Dagley LF, Rautela J, Shi W, Putz EM, Stannard K, Zhang JG, Teh C, Firth M, Ushiki T, Andoniou CE, Degli-Esposti MA, Sharp PP, Sanvitale CE, Infusini G, Liau NP, Linossi EM, Burns CJ, Carotta S, Gray DH, Seillet C, Hutchinson DS, Belz GT, Webb AI, Alexander WS, Li SS, Bullock AN, Babon JJ, Smyth MJ, Nicholson SE, Huntington ND. CIS is a potent checkpoint in NK cell-mediated tumor immunity. Nat Immunol 2016; 17(7): 816–824

[31] Huntington ND, Puthalakath H, Gunn P, Naik E, Michalak EM, Smyth MJ, Tabarias H, Degli-Esposti MA, Dewson G, Willis SN, Motoyama N, Huang DC, Nutt SL, Tarlinton DM, Strasser A. Interleukin 15-mediated survival of natural killer cells is determined by interactions among Bim, Noxa and Mcl-1. Nat Immunol 2007; 8(8): 856–863

[32] Oh SC, Kim SE, Jang IH, Kim SM, Lee SY, Lee S, Chu IS, Yoon SR, Jung H, Choi I, Doh J, Kim TD. NgR1 is an NK cell inhibitory receptor that destabilizes the immunological synapse. Nat Immunol 2023; 24(3): 463–473

[33] Berrien-Elliott MM, Jacobs MT, Fehniger TA. Allogeneic natural killer cell therapy. Blood 2023; 141(8): 856–868

[34] Zhou Y, Cheng L, Liu L, Li X. NK cells are never alone: crosstalk and communication in tumour microenvironments. Mol Cancer 2023; 22(1): 34

[35] Morgan HJ, Rees E, Lanfredini S, Powell KA, Gore J, Gibbs A, Lovatt C, Davies GE, Olivero C, Shorning BY, Tornillo G, Tonks A, Darley R, Wang EC, Patel GK. CD200 ectodomain shedding into the tumor microenvironment leads to NK cell dysfunction and apoptosis. J Clin Invest 2022; 132(21): e150750

[36] Qian S, Wei Z, Yang W, Huang J, Yang Y, Wang J. The role of BCL-2 family proteins in regulating apoptosis and cancer therapy. Front Oncol 2022; 12: 985363

[37] Potluri V, Noothi SK, Vallabhapurapu SD, Yoon SO, Driscoll JJ, Lawrie CH, Vallabhapurapu S. Transcriptional repression of Bim by a novel YY1-RelA complex is essential for the survival and growth of multiple myeloma. PLoS One 2013; 8(7): e66121

[38] Salmanidis M, Brumatti G, Narayan N, Green BD, van den Bergen JA, Sandow JJ, Bert AG, Silke N, Sladic R, Puthalakath H, Rohrbeck L, Okamoto T, Bouillet P, Herold MJ, Goodall GJ, Jabbour AM, Ekert PG. Hoxb8 regulates expression of microRNAs to control cell death and differentiation. Cell Death Differ 2013; 20(10): 1370–1380

[39] Ridinger-Saison M, Evanno E, Gallais I, Rimmele P, Selimoglu-Buet D, Sapharikas E, Moreau-Gachelin F, Guillouf C. Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia. Cell Death Differ 2013; 20(9): 1268–1278

[40] Liu K, Liu F, Zhang N, Liu S, Jiang Y. Pokemon silencing leads to Bim-mediated anoikis of human hepatoma cell QGY7703. Int J Mol Sci 2012; 13(5): 5818–5831

[41] Chen K, Tu Y, Zhang Y, Blair HC, Zhang L, Wu C. PINCH-1 regulates the ERK-Bim pathway and contributes to apoptosis resistance in cancer cells. J Biol Chem 2008; 283(5): 2508–2517

[42] Zhao Z, Zheng J, Ye Y, Zhao K, Wang R, Wang R. MicroRNA-25-3p regulates human nucleus pulposus cell proliferation and apoptosis in intervertebral disc degeneration by targeting Bim. Mol Med Rep 2020; 22: 3621–3628

[43] Chen Z, Chen LY, Dai HY, Wang P, Gao S, Wang K. miR-301a promotes pancreatic cancer cell proliferation by directly inhibiting Bim expression. J Cell Biochem 2012; 113(10): 3229–3235

[44] Zhang H, Zuo Z, Lu X, Wang L, Wang H, Zhu Z. miR-25 regulates apoptosis by targeting Bim in human ovarian cancer. Oncol Rep 2012; 27: 594–598

[45] Dávila D, Jimenez-Mateos EM, Mooney CM, Velasco G, Henshall DC, Prehn JH. Hsp27 binding to the 3′UTR of bim mRNA prevents neuronal death during oxidative stress-induced injury: a novel cytoprotective mechanism. Mol Biol Cell 2014; 25(21): 3413–3423

[46] Puthalakath H, Huang DC, O’Reilly LA, King SM, Strasser A. The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol Cell 1999; 3(3): 287–296

[47] Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, Korsmeyer SJ. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell 2001; 8(3): 705–711

[48] Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F, Adams JM, Strasser A. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 1999; 286(5445): 1735–1738

[49] Erlacher M, Labi V, Manzl C, Bock G, Tzankov A, Hacker G, Michalak E, Strasser A, Villunger A. Puma cooperates with Bim, the rate-limiting BH3-only protein in cell death during lymphocyte development, in apoptosis induction. J Exp Med 2006; 203(13): 2939–2951

[50] Snow AL, Oliveira JB, Zheng L, Dale JK, Fleisher TA, Lenardo MJ. Critical role for BIM in T cell receptor restimulation-induced death. Biol Direct 2008; 3(1): 34

[51] Kurtulus S, Sholl A, Toe J, Tripathi P, Raynor J, Li KP, Pellegrini M, Hildeman DA. Bim controls IL-15 availability and limits engagement of multiple BH3-only proteins. Cell Death Differ 2015; 22(1): 174–184

[52] Grayson JM, Weant AE, Holbrook BC, Hildeman D. Role of Bim in regulating CD8⁺ T-cell responses during chronic viral infection. J Virol 2006; 80(17): 8627–8638

[53] Tsukamoto H, Huston GE, Dibble J, Duso DK, Swain SL. Bim dictates naive CD4 T cell lifespan and the development of age-associated functional defects. J Immunol 2010; 185(8): 4535–4544

[54] Liu R, King A, Bouillet P, Tarlinton DM, Strasser A, Heierhorst J. Proapoptotic BIM impacts B lymphoid homeostasis by limiting the survival of mature B cells in a cell-autonomous manner. Front Immunol 2018; 9: 592

[55] Fischer SF, Bouillet P, O’Donnell K, Light A, Tarlinton DM, Strasser A. Proapoptotic BH3-only protein Bim is essential for developmentally programmed death of germinal center-derived memory B cells and antibody-forming cells. Blood 2007; 110(12): 3978–3984

[56] Sugimoto-Ishige A, Harada M, Tanaka M, Terooatea T, Adachi Y, Takahashi Y, Tanaka T, Burrows PD, Hikida M, Takemori T. Bim establishes the B-cell repertoire from early to late in the immune response. Int Immunol 2021; 33(2): 79–90

[57] Min-Oo G, Bezman NA, Madera S, Sun JC, Lanier LL. Proapoptotic Bim regulates antigen-specific NK cell contraction and the generation of the memory NK cell pool after cytomegalovirus infection. J Exp Med 2014; 211(7): 1289–1296

[58] Tang R, Langdon WY, Zhang J. Regulation of immune responses by E3 ubiquitin ligase Cbl-b. Cell Immunol 2019; 340: 103878

[59] Fang D, Wang HY, Fang N, Altman Y, Elly C, Liu YC. Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. J Biol Chem 2001; 276(7): 4872–4878

[60] Zhao Y, Guo H, Qiao G, Zucker M, Langdon WY, Zhang J. E3 ubiquitin ligase Cbl-b regulates thymic-derived CD4⁺CD25⁺ regulatory T cell development by targeting Foxp3 for ubiquitination. J Immunol 2015; 194(4): 1639–1645

[61] Zhu LL, Luo TM, Xu X, Guo YH, Zhao XQ, Wang TT, Tang B, Jiang YY, Xu JF, Lin X, Jia XM. E3 ubiquitin ligase Cbl-b negatively regulates C-type lectin receptor-mediated antifungal innate immunity. J Exp Med 2016; 213(8): 1555–1570

[62] Wirnsberger G, Zwolanek F, Asaoka T, Kozieradzki I, Tortola L, Wimmer RA, Kavirayani A, Fresser F, Baier G, Langdon WY, Ikeda F, Kuchler K, Penninger JM. Inhibition of CBLB protects from lethal Candida albicans sepsis. Nat Med 2016; 22(8): 915–923

[63] Xiao Y, Tang J, Guo H, Zhao Y, Tang R, Ouyang S, Zeng Q, Rappleye CA, Rajaram MV, Schlesinger LS, Tao L, Brown GD, Langdon WY, Li BT, Zhang J. Targeting CBLB as a potential therapeutic approach for disseminated candidiasis. Nat Med 2016; 22(8): 906–914

[64] Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, Jamieson AM, Langdon WY, Ikeda F, Fededa JP, Cronin SJ, Nitsch R, Schultz-Fademrecht C, Eickhoff J, Menninger S, Unger A, Torka R, Gruber T, Hinterleitner R, Baier G, Wolf D, Ullrich A, Klebl BM, Penninger JM. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 2014; 507(7493): 508–512

[65] Cooper MA, Bush JE, Fehniger TA, VanDeusen JB, Waite RE, Liu Y, Aguila HL, Caligiuri MA. In vivo evidence for a dependence on interleukin 15 for survival of natural killer cells. Blood 2002; 100(10): 3633–3638

[66] Kennedy MK, Glaccum M, Brown SN, Butz EA, Viney JL, Embers M, Matsuki N, Charrier K, Sedger L, Willis CR, Brasel K, Morrissey PJ, Stocking K, Schuh JC, Joyce S, Peschon JJ. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med 2000; 191(5): 771–780

[67] Burkett PR, Koka R, Chien M, Chai S, Boone DL, Ma A. Coordinate expression and trans presentation of interleukin (IL)-15Rα and IL-15 supports natural killer cell and memory CD8⁺ T cell homeostasis. J Exp Med 2004; 200(7): 825–834

[68] Schluns KS, Nowak EC, Cabrera-Hernandez A, Puddington L, Lefrancois L, Aguila HL. Distinct cell types control lymphoid subset development by means of IL-15 and IL-15 receptor alpha expression. Proc Natl Acad Sci USA 2004; 101(15): 5616–5621

[69] Mortier E, Woo T, Advincula R, Gozalo S, Ma A. IL-15Rα chaperones IL-15 to stable dendritic cell membrane complexes that activate NK cells via trans presentation. J Exp Med 2008; 205(5): 1213–1225

[70] Bergamaschi C, Bear J, Rosati M, Beach RK, Alicea C, Sowder R, Chertova E, Rosenberg SA, Felber BK, Pavlakis GN. Circulating IL-15 exists as heterodimeric complex with soluble IL-15Rα in human and mouse serum. Blood 2012; 120(1): e1–e8

[71] Imada K, Leonard WJ. The Jak-STAT pathway. Mol Immunol 2000; 37(1-2): 1–11

[72] Sathe P, Delconte RB, Souza-Fonseca-Guimaraes F, Seillet C, Chopin M, Vandenberg CJ, Rankin LC, Mielke LA, Vikstrom I, Kolesnik TB, Nicholson SE, Vivier E, Smyth MJ, Nutt SL, Glaser SP, Strasser A, Belz GT, Carotta S, Huntington ND. Innate immunodeficiency following genetic ablation of Mcl1 in natural killer cells. Nat Commun 2014; 5(1): 4539

[73] Marçais A, Cherfils-Vicini J, Viant C, Degouve S, Viel S, Fenis A, Rabilloud J, Mayol K, Tavares A, Bienvenu J, Gangloff YG, Gilson E, Vivier E, Walzer T. The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nat Immunol 2014; 15(8): 749–757

[74] Krebs DL, Hilton DJ. SOCS proteins: negative regulators of cytokine signaling. Stem Cells 2001; 19(5): 378–387

[75] Palmer DC, Restifo NP. Suppressors of cytokine signaling (SOCS) in T cell differentiation, maturation, and function. Trends Immunol 2009; 30(12): 592–602

[76] Linossi EM, Babon JJ, Hilton DJ, Nicholson SE. Suppression of cytokine signaling: the SOCS perspective. Cytokine Growth Factor Rev 2013; 24(3): 241–248

[77] Palmer DC, Guittard GC, Franco Z, Crompton JG, Eil RL, Patel SJ, Ji Y, Van Panhuys N, Klebanoff CA, Sukumar M, Clever D, Chichura A, Roychoudhuri R, Varma R, Wang E, Gattinoni L, Marincola FM, Balagopalan L, Samelson LE, Restifo NP. Cish actively silences TCR signaling in CD8⁺ T cells to maintain tumor tolerance. J Exp Med 2015; 212(12): 2095–2113

[78] Lv J, Qin L, Zhao R, Wu D, Wu Z, Zheng D, Li S, Luo M, Wu Q, Long Y, Tang Z, Tang YL, Luo X, Yao Y, Yang LH, Li P. Disruption of CISH promotes the antitumor activity of human T cells and decreases PD-1 expression levels. Mol Ther Oncolytics 2023; 28: 46–58

[79] Miah MA, Yoon CH, Kim J, Jang J, Seong YR, Bae YS. CISH is induced during DC development and regulates DC-mediated CTL activation. Eur J Immunol 2012; 42(1): 58–68

[80] Shoger KE, Cheemalavagu N, Cao YM, Michalides BA, Chaudhri VK, Cohen JA, Singh H, Gottschalk RA. CISH attenuates homeostatic cytokine signaling to promote lung-specific macrophage programming and function. Sci Signal 2021; 14(698): eabe5137

[81] Delconte RB, Kolesnik TB, Dagley LF, Rautela J, Shi W, Putz EM, Stannard K, Zhang JG, Teh C, Firth M, Ushiki T, Andoniou CE, Degli-Esposti MA, Sharp PP, Sanvitale CE, Infusini G, Liau NPD, Linossi EM, Burns CJ, Carotta S, Gray DHD, Seillet C, Hutchinson DS, Belz GT, Webb AI, Alexander WS, Li SS, Bullock AN, Babon JJ, Smyth MJ, Nicholson SE, Huntington ND. CIS is a potent checkpoint in NK cell-mediated tumor immunity. Nat Immunol 2016; 17(7): 816–824

[82] Souza-Fonseca-Guimaraes F, Rossi GR, Dagley LF, Foroutan M, McCulloch TR, Yousef J, Park HY, Gunter JH, Beavis PA, Lin CY, Hediyeh-Zadeh S, Camilleri T, Davis MJ, Huntington ND. TGFβ and CIS inhibition overcomes NK-cell suppression to restore antitumor immunity. Cancer Immunol Res 2022; 10(9): 1047–1054

[83] Zhu H, Blum RH, Bernareggi D, Ask EH, Wu Z, Hoel HJ, Meng Z, Wu C, Guan KL, Malmberg KJ, Kaufman DS. Metabolic reprograming via deletion of CISH in human iPSC-derived NK cells promotes in vivo persistence and enhances anti-tumor activity. Cell Stem Cell 2020; 27(2): 224–237.e6

[84] Daher M, Basar R, Gokdemir E, Baran N, Uprety N, Nunez Cortes AK, Mendt M, Kerbauy LN, Banerjee PP, Sanabria MH, Imahashi N, Li L, Wei Inng Lim FL, Fathi M, Rezvan A, Mohanty V, Shen Y, Shaim H, Lu J, Ozcan G, Ensley E, Kaplan M, Nandivada V, Bdaiwi M, Acharya S, Xi Y, Wan X, Mak D, Liu E, Ang S, Muniz-Feliciano L, Li Y, Wang J, Kordasti S, Petrov N, Varadarajan N, Marin D, Brunetti L, Skinner RJ, Lyu S, Silva L, Turk R, Schubert MS, Rettig GR, McNeill MS, Kurgan G, Behlke MA, Li H, Fowlkes NW, Chen K, Konopleva M, Champlin R, Shpall EJ, Rezvani K. Targeting a cytokine checkpoint enhances the fitness of armored cord blood CAR-NK cells. Blood 2021; 137(5): 624–636

[85] Nakazawa T, Morimoto T, Maeoka R, Matsuda R, Nakamura M, Nishimura F, Ouji N, Yamada S, Nakagawa I, Park YS, Ito T, Nakase H, Tsujimura T. CIS deletion by CRISPR/Cas9 enhances human primary natural killer cell functions against allogeneic glioblastoma. J Exp Clin Cancer Res 2023; 42(1): 205

[86] Bi J, Huang C, Jin X, Zheng C, Huang Y, Zheng X, Tian Z, Sun H. TIPE2 deletion improves the therapeutic potential of adoptively transferred NK cells. J Immunother Cancer 2023; 11(2): e006002

[87] Duan R, Du W, Guo W. EZH2: a novel target for cancer treatment. J Hematol Oncol 2020; 13(1): 104

[88] Parreno V, Martinez AM, Cavalli G. Mechanisms of polycomb group protein function in cancer. Cell Res 2022; 32(3): 231–253

[89] Han Z, Xing X, Hu M, Zhang Y, Liu P, Chai J. Structural basis of EZH2 recognition by EED. Structure 2007; 15(10): 1306–1315

[90] Pan MR, Hsu MC, Chen LT, Hung WC. Orchestration of H3K27 methylation: mechanisms and therapeutic implication. Cell Mol Life Sci 2018; 75(2): 209–223

[91] Kuzmichev A, Nishioka K, Erdjument-Bromage H, Tempst P, Reinberg D. Histone methyltransferase activity associated with a human multiprotein complex containing the enhancer of zeste protein. Genes Dev 2002; 16(22): 2893–2905

[92] Margueron R, Justin N, Ohno K, Sharpe ML, Son J, Drury WJ 3rd, Voigt P, Martin SR, Taylor WR, De Marco V, Pirrotta V, Reinberg D, Gamblin SJ. Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 2009; 461(7265): 762–767

[93] Cao R, Zhang Y. SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol Cell 2004; 15(1): 57–67

[94] He S, Liu Y, Meng L, Sun H, Wang Y, Ji Y, Purushe J, Chen P, Li C, Madzo J, Issa JP, Soboloff J, Reshef R, Moore B, Gattinoni L, Zhang Y. Ezh2 phosphorylation state determines its capacity to maintain CD8⁺ T memory precursors for antitumor immunity. Nat Commun 2017; 8(1): 2125

[95] Kakaradov B, Arsenio J, Widjaja CE, He Z, Aigner S, Metz PJ, Yu B, Wehrens EJ, Lopez J, Kim SH, Zuniga EI, Goldrath AW, Chang JT, Yeo GW. Early transcriptional and epigenetic regulation of CD8⁺ T cell differentiation revealed by single-cell RNA sequencing. Nat Immunol 2017; 18(4): 422–432

[96] Goswami S, Apostolou I, Zhang J, Skepner J, Anandhan S, Zhang X, Xiong L, Trojer P, Aparicio A, Subudhi SK, Allison JP, Zhao H, Sharma P. Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy. J Clin Invest 2018; 128(9): 3813–3818

[97] Wang D, Quiros J, Mahuron K, Pai CC, Ranzani V, Young A, Silveria S, Harwin T, Abnousian A, Pagani M, Rosenblum MD, Van Gool F, Fong L, Bluestone JA, DuPage M. Targeting EZH2 reprograms intratumoral regulatory T cells to enhance cancer immunity. Cell Rep 2018; 23(11): 3262–3274

[98] Chen X, Cao G, Wu J, Wang X, Pan Z, Gao J, Tian Q, Xu L, Li Z, Hao Y, Huang Q, Wang P, Xiao M, Xie L, Tang S, Liu Z, Hu L, Tang J, He R, Wang L, Zhou X, Wu Y, Chen M, Sun B, Zhu B, Huang J, Ye L. The histone methyltransferase EZH2 primes the early differentiation of follicular helper T cells during acute viral infection. Cell Mol Immunol 2020; 17(3): 247–260

[99] Li F, Zeng Z, Xing S, Gullicksrud JA, Shan Q, Choi J, Badovinac VP, Crotty S, Peng W, Xue HH. Ezh2 programs T(FH) differentiation by integrating phosphorylation-dependent activation of Bcl6 and polycomb-dependent repression of p19Arf. Nat Commun 2018; 9(1): 5452

[100] Zhang X, Wang Y, Yuan J, Li N, Pei S, Xu J, Luo X, Mao C, Liu J, Yu T, Gan S, Zheng Q, Liang Y, Guo W, Qiu J, Constantin G, Jin J, Qin J, Xiao Y. Macrophage/microglial Ezh2 facilitates autoimmune inflammation through inhibition of Socs3. J Exp Med 2018; 215(5): 1365–1382

[101] Herviou L, Jourdan M, Martinez AM, Cavalli G, Moreaux J. EZH2 is overexpressed in transitional preplasmablasts and is involved in human plasma cell differentiation. Leukemia 2019; 33(8): 2047–2060

[102] Scharer CD, Barwick BG, Guo M, Bally APR, Boss JM. Plasma cell differentiation is controlled by multiple cell division-coupled epigenetic programs. Nat Commun 2018; 9(1): 1698

[103] Guo M, Price MJ, Patterson DG, Barwick BG, Haines RR, Kania AK, Bradley JE, Randall TD, Boss JM, Scharer CD. EZH2 represses the B cell transcriptional program and regulates antibody-secreting cell metabolism and antibody production. J Immunol 2018; 200(3): 1039–1052

[104] Caganova M, Carrisi C, Varano G, Mainoldi F, Zanardi F, Germain PL, George L, Alberghini F, Ferrarini L, Talukder AK, Ponzoni M, Testa G, Nojima T, Doglioni C, Kitamura D, Toellner KM, Su IH, Casola S. Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J Clin Invest 2013; 123(12): 5009–5022

[105] Béguelin W, Popovic R, Teater M, Jiang Y, Bunting KL, Rosen M, Shen H, Yang SN, Wang L, Ezponda T, Martinez-Garcia E, Zhang H, Zheng Y, Verma SK, McCabe MT, Ott HM, Van Aller GS, Kruger RG, Liu Y, McHugh CF, Scott DW, Chung YR, Kelleher N, Shaknovich R, Creasy CL, Gascoyne RD, Wong KK, Cerchietti L, Levine RL, Abdel-Wahab O, Licht JD, Elemento O, Melnick AM. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell 2013; 23(5): 677–692

[106] Tumes DJ, Onodera A, Suzuki A, Shinoda K, Endo Y, Iwamura C, Hosokawa H, Koseki H, Tokoyoda K, Suzuki Y, Motohashi S, Nakayama T. The polycomb protein Ezh2 regulates differentiation and plasticity of CD4⁺ T helper type 1 and type 2 cells. Immunity 2013; 39(5): 819–832

[107] Huang S, Wang Z, Zhou J, Huang J, Zhou L, Luo J, Wan YY, Long H, Zhu B. EZH2 inhibitor GSK126 suppresses antitumor immunity by driving production of myeloid-derived suppressor cells. Cancer Res 2019; 79(8): 2009–2020

[108] Yin J, Leavenworth JW, Li Y, Luo Q, Xie H, Liu X, Huang S, Yan H, Fu Z, Zhang LY, Zhang L, Hao J, Wu X, Deng X, Roberts CWM, Orkin SH, Cantor H, Wang X. Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity. Proc Natl Acad Sci USA 2015; 112(52): 15988–15993

[109] Bian X, Jiang H, Meng Y, Li YP, Fang J, Lu Z. Regulation of gene expression by glycolytic and gluconeogenic enzymes. Trends Cell Biol 2022; 32(9): 786–799

[110] Choe JY, Poland BW, Fromm HJ, Honzatko RB. Role of a dynamic loop in cation activation and allosteric regulation of recombinant porcine fructose-1,6-bisphosphatase. Biochemistry 1998; 37(33): 11441–11450

[111] Gidh-Jain M, Zhang Y, van Poelje PD, Liang JY, Huang S, Kim J, Elliott JT, Erion MD, Pilkis SJ, Raafat el-Maghrabi M. The allosteric site of human liver fructose-1,6-bisphosphatase. Analysis of six AMP site mutants based on the crystal structure. J Biol Chem 1994; 269(44): 27732–27738

[112] Ke H, Thorpe CM, Seaton BA, Marcus F, Lipscomb WN. Molecular structure of fructose-1,6-bisphosphatase at 2.8-Å resolution. Proc Natl Acad Sci USA 1989; 86(5): 1475–1479

[113] Sharma AG, Kanwal SK, Chhapola V, Kumar V. Novel fructose bisphosphatase 1 gene mutation presenting as recurrent episodes of vomiting in an Indian child. J Postgrad Med 2018; 64(3): 180–182

[114] Li B, Qiu B, Lee DS, Walton ZE, Ochocki JD, Mathew LK, Mancuso A, Gade TP, Keith B, Nissim I, Simon MC. Fructose-1, 6-bisphosphatase opposes renal carcinoma progression. Nature 2014; 513(7517): 251–255

[115] Dong C, Yuan T, Wu Y, Wang Y, Fan TW, Miriyala S, Lin Y, Yao J, Shi J, Kang T, Lorkiewicz P, St Clair D, Hung MC, Evers BM, Zhou BP. Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell 2013; 23(3): 316–331

[116] Goldsmith JR, Chen YH. Regulation of inflammation and tumorigenesis by the TIPE family of phospholipid transfer proteins. Cell Mol Immunol 2017; 14(6): 482–487

[117] Xu L, Pan F, Guo Z. TIPE2: a candidate for targeting antitumor immunotherapy. J Immunol 2024; 212(5): 755–763

[118] Gao J, Zhang H, Zhang F. Research progress of TIPE2 in immune-related diseases. Int Immunopharmacol 2023; 121: 110514

[119] Fayngerts SA, Wu J, Oxley CL, Liu X, Vourekas A, Cathopoulis T, Wang Z, Cui J, Liu S, Sun H, Lemmon MA, Zhang L, Shi Y, Chen YH. TIPE3 is the transfer protein of lipid second messengers that promote cancer. Cancer Cell 2014; 26(4): 465–478

[120] Yang M, Zhao Q, Wang X, Liu T, Yao G, Lou C, Zhang Y. TNFAIP8 overexpression is associated with lymph node metastasis and poor prognosis in intestinal-type gastric adenocarcinoma. Histopathology 2014; 65(4): 517–526

[121] Wang L, Song Y, Men X. Variance of TNFAIP8 expression between tumor tissues and tumor-infiltrating CD4⁺ and CD8⁺ T cells in non-small cell lung cancer. Tumour Biol 2014; 35(3): 2319–2325

[122] Ma Y, Liu X, Wei Z, Wang X, Wang Z, Zhong W, Li Y, Zhu F, Guo C, Zhang L, Wang X. The expression and significance of TIPE2 in peripheral blood mononuclear cells from asthmatic children. Scand J Immunol 2013; 78(6): 523–528

[123] Zhang C, Kallakury BV, Ross JS, Mewani RR, Sheehan CE, Sakabe I, Luta G, Kumar D, Yadavalli S, Starr J, Sreenath TL, Srivastava S, Pollard HB, Eidelman O, Srivastava M, Kasid UN. The significance of TNFAIP8 in prostate cancer response to radiation and docetaxel and disease recurrence. Int J Cancer 2013; 133(1): 31–42

[124] Xi W, Hu Y, Liu Y, Zhang J, Wang L, Lou Y, Qu Z, Cui J, Zhang G, Liang X, Ma C, Gao C, Chen Y, Liu S. Roles of TIPE2 in hepatitis B virus-induced hepatic inflammation in humans and mice. Mol Immunol 2011; 48(9-10): 1203–1208

[125] Sun H, Gong S, Carmody RJ, Hilliard A, Li L, Sun J, Kong L, Xu L, Hilliard B, Hu S, Shen H, Yang X, Chen YH. TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis. Cell 2008; 133(3): 415–426

[126] Yan D, Wang J, Sun H, Zamani A, Zhang H, Chen W, Tang A, Ruan Q, Yang X, Chen YH, Wan X. TIPE2 specifies the functional polarization of myeloid-derived suppressor cells during tumorigenesis. J Exp Med 2020; 217(2): e20182005

[127] Zhang X, Wang J, Fan C, Li H, Sun H, Gong S, Chen YH, Shi Y. Crystal structure of TIPE2 provides insights into immune homeostasis. Nat Struct Mol Biol 2009; 16(1): 89–90

[128] Gus-Brautbar Y, Johnson D, Zhang L, Sun H, Wang P, Zhang S, Zhang L, Chen YH. The anti-inflammatory TIPE2 is an inhibitor of the oncogenic Ras. Mol Cell 2012; 45(5): 610–618

[129] Cao X, Zhang L, Shi Y, Sun Y, Dai S, Guo C, Zhu F, Wang Q, Wang J, Wang X, Chen YH, Zhang L. Human tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 suppresses hepatocellular carcinoma metastasis through inhibiting Rac1. Mol Cancer 2013; 12(1): 149

[130] Sun H, Zhuang G, Chai L, Wang Z, Johnson D, Ma Y, Chen YH. TIPE2 controls innate immunity to RNA by targeting the phosphatidylinositol 3-kinase-Rac pathway. J Immunol 2012; 189(6): 2768–2773

[131] Wang Z, Fayngerts S, Wang P, Sun H, Johnson DS, Ruan Q, Guo W, Chen YH. TIPE2 protein serves as a negative regulator of phagocytosis and oxidative burst during infection. Proc Natl Acad Sci USA 2012; 109(38): 15413–15418

[132] Zhang Y, Mei S, Zhou Y, Yang D, Pan T, Chen Z, Wang Q. TIPE2 negatively regulates mycoplasma pneumonia-triggered immune response via MAPK signaling pathway. Sci Rep 2017; 7(1): 13319

[133] Falasca M, Liu R, Fan T, Geng W, Chen YH, Ruan Q, Zhang C. Negative immune regulator TIPE2 promotes M2 macrophage differentiation through the activation of PI3K-AKT signaling pathway. PLoS One 2017; 12(1): e0170666

[134] Luan Y, Yao Y, Zhang L, Dong N, Zhang Q, Yu Y, Sheng Z. Expression of tumor necrosis factor-α induced protein 8 like-2 contributes to the immunosuppressive property of CD4⁺CD25⁺ regulatory T cells in mice. Mol Immunol 2011; 49(1–2): 219–226

[135] Bi J, Cheng C, Zheng C, Huang C, Zheng X, Wan X, Chen YH, Tian Z, Haoyu S. TIPE2 is a checkpoint of natural killer cell maturation and antitumor immunity. Sci Adv 2021; 7(38): eabi6515

[136] Bi J, Jin X, Zheng C, Huang C, Zhong C, Zheng X, Tian Z, Sun H. Checkpoint TIPE2 limits the helper functions of NK cells in supporting antitumor CD8⁺ T cells. Adv Sci (Weinh) 2023; 10(12): 2207499

[137] McGettrick AF, O’Neill LAJ. The role of HIF in immunity and inflammation. Cell Metab 2020; 32(4): 524–536

[138] Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O₂ tension. Proc Natl Acad Sci USA 1995; 92(12): 5510–5514

[139] Wu Q, You L, Nepovimova E, Heger Z, Wu W, Kuca K, Adam V. Hypoxia-inducible factors: master regulators of hypoxic tumor immune escape. J Hematol Oncol 2022; 15(1): 77

[140] Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS. HIF-1α is essential for myeloid cell-mediated inflammation. Cell 2003; 112(5): 645–657

[141] Peyssonnaux C, Cejudo-Martin P, Doedens A, Zinkernagel AS, Johnson RS, Nizet V. Cutting edge: essential role of hypoxia inducible factor-1α in development of lipopolysaccharide-induced sepsis. J Immunol 2007; 178(12): 7516–7519

[142] Wang T, Liu H, Lian G, Zhang SY, Wang X, Jiang C. HIF1α-induced glycolysis metabolism is essential to the activation of inflammatory macrophages. Mediators Inflamm 2017; 2017: 9029327

[143] Liu J, Zhang X, Chen K, Cheng Y, Liu S, Xia M, Chen Y, Zhu H, Li Z, Cao X. CCR7 chemokine receptor-inducible lnc-Dpf3 restrains dendritic cell migration by inhibiting HIF-1α-mediated glycolysis. Immunity 2019; 50(3): 600–615.e15

[144] Köhler T, Reizis B, Johnson RS, Weighardt H, Forster I. Influence of hypoxia-inducible factor 1α on dendritic cell differentiation and migration. Eur J Immunol 2012; 42(5): 1226–1236

[145] Burczyk G, Cichon I, Kolaczkowska E. Itaconate suppresses formation of neutrophil extracellular traps (NETs): involvement of hypoxia-inducible factor 1α (Hif-1α) and heme oxygenase (HO-1). Front Immunol 2022; 13: 864638

[146] Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T, Sobolewski A, Condliffe AM, Cowburn AS, Johnson N, Chilvers ER. Hypoxia-induced neutrophil survival is mediated by HIF-1α-dependent NF-κB activity. J Exp Med 2005; 201(1): 105–115

[147] Mecklenburgh KI, Walmsley SR, Cowburn AS, Wiesener M, Reed BJ, Upton PD, Deighton J, Greening AP, Chilvers ER. Involvement of a ferroprotein sensor in hypoxia-mediated inhibition of neutrophil apoptosis. Blood 2002; 100(8): 3008–3016

[148] Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen HR, Luo W, Zeller K, Shimoda L, Topalian SL, Semenza GL, Dang CV, Pardoll DM, Pan F. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 2011; 146(5): 772–784

[149] Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H. HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 2011; 208(7): 1367–1376

[150] Thiel M, Caldwell CC, Kreth S, Kuboki S, Chen P, Smith P, Ohta A, Lentsch AB, Lukashev D, Sitkovsky MV. Targeted deletion of HIF-1α gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival. PLoS One 2007; 2(9): e853

[151] Qian T, Hong J, Wang L, Wang Z, Lu Z, Li Y, Liu R, Chu Y. Regulation of CD11b by HIF-1α and the STAT3 signaling pathway contributes to the immunosuppressive function of B cells in inflammatory bowel disease. Mol Immunol 2019; 111: 162–171

[152] Meng X, Grotsch B, Luo Y, Knaup KX, Wiesener MS, Chen XX, Jantsch J, Fillatreau S, Schett G, Bozec A. Hypoxia-inducible factor-1α is a critical transcription factor for IL-10-producing B cells in autoimmune disease. Nat Commun 2018; 9(1): 251

[153] Liu X, Jiang X, Liu R, Wang L, Qian T, Zheng Y, Deng Y, Huang E, Xu F, Wang JY, Chu Y. B cells expressing CD11b effectively inhibit CD4⁺ T-cell responses and ameliorate experimental autoimmune hepatitis in mice. Hepatology 2015; 62(5): 1563–1575

[154] Kojima H, Gu H, Nomura S, Caldwell CC, Kobata T, Carmeliet P, Semenza GL, Sitkovsky MV. Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1α-deficient chimeric mice. Proc Natl Acad Sci USA 2002; 99(4): 2170–2174

[155] Ni J, Wang X, Stojanovic A, Zhang Q, Wincher M, Buhler L, Arnold A, Correia MP, Winkler M, Koch PS, Sexl V, Hofer T, Cerwenka A. Single-cell RNA sequencing of tumor-infiltrating NK cells reveals that inhibition of transcription factor HIF-1α unleashes NK cell activity. Immunity 2020; 52(6): 1075–1087.e8

[156] Sharma P, Goswami S, Raychaudhuri D, Siddiqui BA, Singh P, Nagarajan A, Liu J, Subudhi SK, Poon C, Gant KL, Herbrich SM, Anandhan S, Islam S, Amit M, Anandappa G, Allison JP. Immune checkpoint therapy—current perspectives and future directions. Cell 2023; 186(8): 1652–1669

[157] Zhang C, Hu Y, Xiao W, Tian Z. Chimeric antigen receptor- and natural killer cell receptor-engineered innate killer cells in cancer immunotherapy. Cell Mol Immunol 2021; 18(9): 2083–2100

[158] Yin J, Leavenworth JW, Li Y, Luo Q, Xie H, Liu X, Huang S, Yan H, Fu Z, Zhang LY, Zhang L, Hao J, Wu X, Deng X, Roberts CW, Orkin SH, Cantor H, Wang X. Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity. Proc Natl Acad Sci USA 2015; 112(52): 15988–15993

[159] Bernard PL, Delconte R, Pastor S, Laletin V, Costa Da Silva C, Goubard A, Josselin E, Castellano R, Krug A, Vernerey J, Devillier R, Olive D, Verhoeyen E, Vivier E, Huntington ND, Nunes J, Guittard G. Targeting CISH enhances natural cytotoxicity receptor signaling and reduces NK cell exhaustion to improve solid tumor immunity. J Immunother Cancer 2022; 10(5): e004244

[160] Nakazawa T, Morimoto T, Maeoka R, Matsuda R, Nakamura M, Nishimura F, Ouji N, Yamada S, Nakagawa I, Park YS, Ito T, Nakase H, Tsujimura T. CIS deletion by CRISPR/Cas9 enhances human primary natural killer cell functions against allogeneic glioblastoma. J Exp Clin Cancer Res 2023; 42(1): 205

[161] Zhu H, Blum RH, Bernareggi D, Ask EH, Wu Z, Hoel HJ, Meng Z, Wu C, Guan KL, Malmberg KJ, Kaufman DS. Metabolic reprograming via deletion of CISH in human iPSC-derived NK cells promotes in vivo persistence and enhances anti-tumor activity. Cell Stem Cell 2020; 27(2): 224–237.e6

[162] Bi J, Cheng C, Zheng C, Huang C, Zheng X, Wan X, Chen YH, Tian Z, Sun H. TIPE2 is a checkpoint of natural killer cell maturation and antitumor immunity. Sci Adv 2021; 7(38): eabi6515

[163] Afolabi LO, Adeshakin AO, Sani MM, Bi J, Wan X. Genetic reprogramming for NK cell cancer immunotherapy with CRISPR/Cas9. Immunology 2019; 158(2): 63–69

[164] Huang RS, Lai MC, Shih HA, Lin S. A robust platform for expansion and genome editing of primary human natural killer cells. J Exp Med 2021; 218(3): e20201529

[165] Rautela J, Surgenor E, Huntington ND. Drug target validation in primary human natural killer cells using CRISPR RNP. J Leukoc Biol 2020; 108(4): 1397–1408

Acknowledgements

This work was supported by the National Key R&D Program of China (No. 2020YFA0710802 to Jiacheng Bi), Guangdong Basic and Applied Basic Research Foundation (No. 2021A1515110174 to Yingying Huang), and the National Natural Science Foundation of China (No. 82071768 to Jiacheng Bi).

Compliance with ethics guidelines

Conflicts of interest Yingying Huang, Zhigang Tian, and Jiacheng Bi declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Zhigang Tian is a member of the Editorial Board of Frontiers of Medicine, who was excluded from the peer-review process and all editorial decisions related to the acceptance and publication of this article. Peer-review was handled independently by the other editors to minimise bias.

This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

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