肾透明细胞癌联合免疫治疗新策略——有氧糖酵解的研究进展及展望

doi:10.19401/j.cnki.1007-3639.2022.04.001

摘要/Abstract

摘要：

肾恶性肿瘤的发病率逐年上升,其中肾透明细胞癌约占所有肾恶性肿瘤的80%,肾透明细胞癌独特的遗传背景和突变特征往往涉及以乏氧信号、糖酵解代谢、氨基酸代谢、线粒体氧化磷酸化等通路为代表的肿瘤微环境（tumor microenvironment,TME）内稳态失调。免疫检查点抑制剂（immune checkpoint inhibitor,ICI）联合酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）已经成为晚期肾透明细胞癌患者的一线治疗方案,但是,联合治疗方案的疗效仍有待提高,且缺乏明确诊断、指导用药、评估预后的生物标志物。近年来,多组学研究从不同层次探索肾透明细胞癌分子通路的异常改变。肾透明细胞癌发生代谢重编程,在氧气充足的情况下也以低效能的糖酵解为能量供应来源,促进自身无限生长,并且有氧糖酵解通路展现的显著异常与不良预后相关。肾透明细胞癌异常的糖酵解信号能促进肿瘤生长,并与TME中的免疫细胞相互作用,使促肿瘤免疫和抗肿瘤免疫平衡失调,造成抑制性免疫微环境,介导肿瘤免疫逃逸,从而对免疫治疗产生不利影响。因此,通过阻断异常糖代谢来抑制肿瘤生长,以有氧糖酵解通路和免疫微环境为切入点,可为肾透明细胞癌以及泛肿瘤治疗提供新的研究方向。然而,如何在复杂的肿瘤免疫微环境中最大程度地将肿瘤细胞代谢重编程转化为用药靶点并运用于临床实践仍待探讨。在肾透明细胞癌中,糖酵解抑制剂联合ICI或TKI作为新方案或能协同发挥抗肿瘤效应,逆转治疗抵抗。本文通过对糖酵解代谢途径中的关键限速酶、转运体及其抑制剂与肿瘤免疫微环境之间的关系进行综述,探讨糖酵解抑制剂在肾透明细胞癌中的作用机制和肿瘤免疫微环境的变化,及其与靶向治疗或免疫治疗联合应用的巨大临床转化价值,未来将为肾透明细胞癌的临床诊疗提供新思路,为患者带来临床获益。

关键词: 肾透明细胞癌, 糖酵解, 代谢重编程, 肿瘤微环境, 免疫治疗

Abstract:

The incidence of renal malignancies is increasing each year. Clear cell renal cell carcinoma (ccRCC) accounts for approximately 80% of all renal malignancies. Its unique genetic background and mutation features involve dysregulation of homeostasis within the tumor microenvironment (TME) represented by pathways such as hypoxic signaling, glycolytic metabolism, amino acid metabolism, and mitochondrial oxidative phosphorylation. Immune checkpoint inhibitor (ICI) in combination with tyrosine kinase inhibitor (TKI) has become the first line of treatment for patients with advanced ccRCC. However, the efficacy of combination therapy has yet to be improved, and there is an urgent need for biomarkers that can assist the diagnosis, treatment, and prognosis. Multi-omics studies have investigated aberrant abnormalities in molecular pathways of ccRCC in recent years. The ccRCC undergoes metabolic reprogramming and prefers inefficient glycolysis as a significant energy source even under normoxia to support unlimited proliferation. In addition, abnormalities in the aerobic glycolytic pathway have been associated with poor prognosis. Dysregulated glycolytic signaling promotes tumor progression and interacts with immune cells within the TME in ccRCC, resulting in an imbalance between pro and antitumor immunity, creating a suppressive immune microenvironment, promoting tumor immune escape, and impairing antitumor effects of immunotherapy. Therefore, integrating the aerobic glycolytic pathway and the immune microenvironment as an entry point, limiting tumor progression by restricting aberrant glycolytic metabolism broadens therapeutic options for ccRCC and pan-cancer treatments. However, further research is required on maximizing the metabolic reprogramming that tumor cells harbor in the complex TME to convert it into a therapeutic target and apply it in clinical practice. Glycolytic inhibitors in combination with ICI or TKI might be a novel strategy that demonstrates synergistic antitumor effects and overcomes resistance in treating human cancers. This review analyzes the correlations between essential rate-limiting enzymes, transporters, glycolytic pathway inhibitors, and the tumor immune microenvironment in ccRCC. Then we summarize the effects of glycolytic inhibitors in human cancers and alterations in the tumor immune microenvironment. Along with the potential clinical translational value in combination with targeted therapy or immunotherapy, targeting glycolysis will provide new insights for the clinical treatment of ccRCC and bring clinical benefits to patients in the future.

Key words: Clear cell renal cell carcinoma, Glycolysis, Metabolic reprogramming, Tumor microenvironment, Immunotherapy

中图分类号:

R737.11

宿佳琦, 徐文浩, 田熙, 艾合太木江·安外尔, 瞿元元, 施国海, 张海梁, 叶定伟. 肾透明细胞癌联合免疫治疗新策略——有氧糖酵解的研究进展及展望[J]. 中国癌症杂志, 2022, 32(4): 287-297.

SU Jiaqi, XU Wenhao, TIAN Xi, ANWAIE Aihetaimujiang, QU Yuanyuan, SHI Guohai, ZHANG Hailiang, YE Dingwei. New strategies for combined with immunotherapy of clear cell renal cell carcinoma: advances in aerobic glycolysis[J]. China Oncology, 2022, 32(4): 287-297.

参考文献 92

[1]	FERLAY J,, COLOMBET M,, SOERJOMATARAM I, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018[J]. Eur J Cancer, 2018, 103: 356-387. doi: 10.1016/j.ejca.2018.07.005
[2]	SIEGEL R L,, MILLER K D,, JEMAL A. Cancer statistics, 2020[J]. CA Cancer J Clin, 2020, 70(1): 7-30. doi: 10.3322/caac.21590
[3]	SUNG H,, FERLAY J,, SIEGEL R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. doi: 10.3322/caac.21660
[4]	SIEGEL R L,, MILLER K D,, FUCHS H E, et al. Cancer statistics, 2021[J]. CA Cancer J Clin, 2021, 71(1): 7-33. doi: 10.3322/caac.21654
[5]	MOCH H,, CUBILLA A L,, HUMPHREY P A, et al. The 2016 WHO classification of tumours of the urinary system and male genital organs-part A: renal, penile, and testicular tumours[J]. Eur Urol, 2016, 70(1): 93-105. doi: 10.1016/j.eururo.2016.02.029
[6]	CAPITANIO U,, CLOUTIER V,, ZINI L, et al. A critical assessment of the prognostic value of clear cell, papillary and chromophobe histological subtypes in renal cell carcinoma: a population-based study[J]. BJU Int, 2009, 103(11): 1496-1500. doi: 10.1111/j.1464-410X.2008.08259.x
[7]	LEIBOVICH B C,, LOHSE C M,, CRISPEN P L, et al. Histological subtype is an independent predictor of outcome for patients with renal cell carcinoma[J]. J Urol, 2010, 183(4): 1309-1315. doi: 10.1016/j.juro.2009.12.035
[8]	KEEGAN K A,, SCHUPP C W,, CHAMIE K, et al. Histopathology of surgically treated renal cell carcinoma: survival differences by subtype and stage[J]. J Urol, 2012, 188(2): 391-397. doi: 10.1016/j.juro.2012.04.006
[9]	HSIEH J J,, LE V H,, OYAMA T, et al. Chromosome 3p loss-orchestrated VHL, HIF, and epigenetic deregulation in clear cell renal cell carcinoma[J]. J Clin Oncol, 2018: JCO2018792549.
[10]	HANAHAN D,, WEINBERG R A. Hallmarks of cancer: the next generation[J]. Cell, 2011, 144(5): 646-674. doi: 10.1016/j.cell.2011.02.013
[11]	HAKIMI A A,, REZNIK E,, LEE C H, et al. An integrated metabolic atlas of clear cell renal cell carcinoma[J]. Cancer Cell, 2016, 29(1): 104-116. doi: 10.1016/j.ccell.2015.12.004
[12]	PAVLOVA N N,, THOMPSON C B. The emerging hallmarks of cancer metabolism[J]. Cell Metab, 2016, 23(1): 27-47. doi: 10.1016/j.cmet.2015.12.006
[13]	WARBURG O. On the origin of cancer cells[J]. Science, 1956, 123(3191): 309-314. doi: 10.1126/science.123.3191.309 pmid: 13298683
[14]	MOORE L E,, NICKERSON M L,, BRENNAN P, et al. Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors[J]. PLoS Genet, 2011, 7(10): e1002312. doi: 10.1371/journal.pgen.1002312
[15]	MASOUD G N,, LI W. HIF-1α pathway: role, regulation and intervention for cancer therapy[J]. Acta Pharm Sin B, 2015, 5(5): 378-389. doi: 10.1016/j.apsb.2015.05.007
[16]	SCHÖNENBERGER D,, HARLANDER S,, RAJSKI M, et al. Formation of renal cysts and tumors in vhl/Trp53-deficient mice requires HIF1α and HIF2α[J]. Cancer Res, 2016, 76(7): 2025-2036. doi: 10.1158/0008-5472.CAN-15-1859
[17]	CANCER GENOME ATLAS RESEARCH NETWORK. Comprehensive molecular characterization of clear cell renal cell carcinoma[J]. Nature, 2013, 499(7456): 43-49. doi: 10.1038/nature12222
[18]	CLARK D J,, DHANASEKARAN S M,, PETRALIA F, et al. Integrated proteogenomic characterization of clear cell renal cell carcinoma[J]. Cell, 2020, 180(1): 207. doi: 10.1016/j.cell.2019.12.026
[19]	COURTNEY K D,, BEZWADA D,, MASHIMO T, et al. Isotope tracing of human clear cell renal cell carcinomas demonstrates suppressed glucose oxidation in vivo[J]. Cell Metab, 2018, 28(5): 793-800.e2. doi: 10.1016/j.cmet.2018.07.020
[20]	CHAN D A,, SUTPHIN P D,, NGUYEN P, et al. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality[J]. Sci Transl Med, 2011, 3(94): 94ra70.
[21]	SUGANUMA N,, SEGADE F,, MATSUZU K, et al. Differential expression of facilitative glucose transporters in normal and tumour kidney tissues[J]. BJU Int, 2007, 99(5): 1143-1149. doi: 10.1111/j.1464-410X.2007.06765.x
[22]	JI Z G,, HUO C Y,, YANG P Q. Genistein inhibited the proliferation of kidney cancer cells via CDKN2a hypomethylation: role of abnormal apoptosis[J]. Int Urol Nephrol, 2020, 52(6): 1049-1055. doi: 10.1007/s11255-019-02372-2
[23]	HIRATA H,, UENO K,, NAKAJIMA K, et al. Genistein downregulates onco-miR-1260b and inhibits Wnt-signalling in renal cancer cells[J]. Br J Cancer, 2013, 108(10): 2070-2078. doi: 10.1038/bjc.2013.173
[24]	OCAÑA M C,, MARTÍNEZ-POVEDA B,, MARÍ-BEFFA M, et al. Fasentin diminishes endothelial cell proliferation, differentiation and invasion in a glucose metabolism-independent manner[J]. Sci Rep, 2020, 10(1): 6132. doi: 10.1038/s41598-020-63232-z
[25]	WU K H,, HO C T,, CHEN Z F, et al. The apple polyphenol phloretin inhibits breast cancer cell migration and proliferation via inhibition of signals by type 2 glucose transporter[J]. J Food Drug Anal, 2018, 26(1): 221-231. doi: 10.1016/j.jfda.2017.03.009
[26]	KRAUS D,, RECKENBEIL J,, VEIT N, et al. Targeting glucose transport and the NAD pathway in tumor cells with STF-31: a re-evaluation[J]. Cell Oncol (Dordr), 2018, 41(5): 485-494.
[27]	SIEBENEICHER H,, CLEVE A,, REHWINKEL H, et al. Identification and optimization of the first highly selective GLUT1 inhibitor BAY-876[J]. Chem Med Chem, 2016, 11(20): 2261-2271. doi: 10.1002/cmdc.201600276
[28]	WEI X H,, MAO T T,, LI S J, et al. DT-13 inhibited the proliferation of colorectal cancer via glycolytic metabolism and AMPK/mTOR signaling pathway[J]. Phytomedicine, 2019, 54: 120-131. doi: 10.1016/j.phymed.2018.09.003
[29]	KARAGEORGIS G,, RECKZEH E S,, CEBALLOS J, et al. Chromopynones are pseudo natural product glucose uptake inhibitors targeting glucose transporters GLUT-1 and-3[J]. Nat Chem, 2018, 10(11): 1103-1111. doi: 10.1038/s41557-018-0132-6
[30]	GUO Z F,, CHENG Z Q,, WANG J X, et al. Discovery of a potent GLUT inhibitor from a library of rapafucins by using 3D microarrays[J]. Angew Chem Int Ed Engl, 2019, 58(48): 17158-17162. doi: 10.1002/anie.201905578
[31]	YOSHINO H,, ENOKIDA H,, ITESAKO T, et al. Tumor-suppressive microRNA-143/145 cluster targets hexokinase-2 in renal cell carcinoma[J]. Cancer Sci, 2013, 104(12): 1567-1574. doi: 10.1111/cas.12280
[32]	SIMON A G,, ESSER L K,, ELLINGER J, et al. Targeting glycolysis with 2-deoxy-D-glucose sensitizes primary cell cultures of renal cell carcinoma to tyrosine kinase inhibitors[J]. J Cancer Res Clin Oncol, 2020, 146(9): 2255-2265. doi: 10.1007/s00432-020-03278-8
[33]	PATRA K C,, WANG Q,, BHASKAR P T, et al. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer[J]. Cancer Cell, 2013, 24(2): 213-228. doi: 10.1016/j.ccr.2013.06.014
[34]	LUO F X,, LI Y,, YUAN F, et al. Hexokinase Ⅱ promotes the Warburg effect by phosphorylating alpha subunit of pyruvate dehydrogenase[J]. Chung Kuo Yen Cheng Yen Chiu, 2019, 31(3): 521-532.
[35]	XU W H,, LIU W R,, XU Y, et al. Hexokinase 3 dysfunction promotes tumorigenesis and immune escape by upregulating monocyte/macrophage infiltration into the clear cell renal cell carcinoma microenvironment[J]. Int J Biol Sci, 2021, 17(9): 2205-2222. doi: 10.7150/ijbs.58295
[36]	NILSSON H,, LINDGREN D,, MANDAHL FORSBERG A, et al. Primary clear cell renal carcinoma cells display minimal mitochondrial respiratory capacity resulting in pronounced sensitivity to glycolytic inhibition by 3-Bromopyruvate[J]. Cell Death Dis, 2015, 6: e1585. doi: 10.1038/cddis.2014.545
[37]	FLORIDI A,, PAGGI M G,, MARCANTE M L, et al. Lonidamine, a selective inhibitor of aerobic glycolysis of murine tumor cells[J]. J Natl Cancer Inst, 1981, 66(3): 497-499.
[38]	STAHL M,, SCHMOLL E,, BECKER H, et al. Lonidamine versus high-dose tamoxifen in progressive, advanced renal cell carcinoma: rsults of an ongoing randomized phase Ⅱ study[J]. Semin Oncol, 1991, 18(2 Suppl 4): 33-37.
[39]	LIU X H,, LI Y H,, WANG K Y, et al. GSH-responsive nanoprodrug to inhibit glycolysis and alleviate immunosuppression for cancer therapy[J]. Nano Lett, 2021, 21(18): 7862-7869. doi: 10.1021/acs.nanolett.1c03089
[40]	LI W,, ZHENG M Z,, WU S P, et al. Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2[J]. J Exp Clin Cancer Res, 2017, 36(1): 58. doi: 10.1186/s13046-017-0530-4
[41]	ZHENG M Z,, WU C R,, YANG K Y, et al. Novel selective hexokinase 2 inhibitor Benitrobenrazide blocks cancer cells growth by targeting glycolysis[J]. Pharmacol Res, 2021, 164: 105367. doi: 10.1016/j.phrs.2020.105367
[42]	LI J,, ZHANG S Q,, LIAO D Z, et al. Overexpression of PFKFB3 promotes cell glycolysis and proliferation in renal cell carcinoma[J]. BMC Cancer, 2022, 22(1): 83. doi: 10.1186/s12885-022-09183-2
[43]	CLEM B,, TELANG S,, CLEM A, et al. Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth[J]. Mol Cancer Ther, 2008, 7(1): 110-120. doi: 10.1158/1535-7163.MCT-07-0482
[44]	CLEM B F,, O'NEAL J,, TAPOLSKY G, et al. Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer[J]. Mol Cancer Ther, 2013, 12(8): 1461-1470. doi: 10.1158/1535-7163.MCT-13-0097
[45]	MONDAL S,, ROY D,, SARKAR BHATTACHARYA S, et al. Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers[J]. Int J Cancer, 2019, 144(1): 178-189. doi: 10.1002/ijc.31868
[46]	GUSTAFSSON N M S,, FÄRNEGÅRDH K,, BONAGAS N, et al. Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination[J]. Nat Commun, 2018, 9(1): 3872. doi: 10.1038/s41467-018-06287-x
[47]	TELANG S,, YADDANADUPI K,, TAPOLSKY G, et al. Abstract 557: taking the sweet out of Th17 cells to potentiate immuno-oncology drugs[C]. Immunology. American Association for Cancer Research, 2016.
[48]	DEY P,, SON J Y,, KUNDU A, et al. Knockdown of pyruvate kinase M2 inhibits cell proliferation, metabolism, and migration in renal cell carcinoma[J]. Int J Mol Sci, 2019, 20(22): E5622.
[49]	HUANG J J,, ZHAO X Y,, LI X, et al. HMGCR inhibition stabilizes the glycolytic enzyme PKM2 to support the growth of renal cell carcinoma[J]. PLoS Biol, 2021, 19(4): e3001197. doi: 10.1371/journal.pbio.3001197
[50]	CHEN J,, XIE J,, JIANG Z, et al. Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2[J]. Oncogene, 2011, 30(42): 4297-4306. doi: 10.1038/onc.2011.137
[51]	SON J Y,, YOON S,, TAE I H, et al. Novel therapeutic roles of MC-4 in combination with everolimus against advanced renal cell carcinoma by dual targeting of Akt/pyruvate kinase muscle isozyme M2 and mechanistic target of rapamycin complex 1 pathways[J]. Cancer Med, 2018, 7(10): 5083-5095. doi: 10.1002/cam4.1748
[52]	SHANKAR BABU M,, MAHANTA S,, LAKHTER A J, et al. Lapachol inhibits glycolysis in cancer cells by targeting pyruvate kinase M2[J]. PLoS One, 2018, 13(2): e0191419.
[53]	ZHOU Y Y,, HUANG Z N,, SU J, et al. Benserazide is a novel inhibitor targeting PKM2 for melanoma treatment[J]. Int J Cancer, 2020, 147(1): 139-151. doi: 10.1002/ijc.32756
[54]	ZAHRA K,, DEY T, ASHISH, et al. Pyruvate kinase M2 and cancer: the role of PKM2 in promoting tumorigenesis[J]. Front Oncol, 2020, 10: 159. doi: 10.3389/fonc.2020.00159
[55]	ANASTASIOU D,, YU Y M,, ISRAELSEN W J, et al. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis[J]. Nat Chem Biol, 2012, 8(10): 839-847. doi: 10.1038/nchembio.1060
[56]	MOHAMMAD G H,, VASSILEVA V,, ACEDO P, et al. Targeting pyruvate kinase M2 and lactate dehydrogenase A is an effective combination strategy for the treatment of pancreatic cancer[J]. Cancers (Basel), 2019, 11(9): E1372.
[57]	WANG X S,, XU L X,, WU Q L, et al. Inhibition of LDHA deliver potential anticancer performance in renal cell carcinoma[J]. Urol Int, 2017, 99(2): 237-244. doi: 10.1159/000445125
[58]	ZEUSCHNER P,, HÖLTERS S,, STÖCKLE M, et al. Thrombospondin-2 and LDH are putative predictive biomarkers for treatment with everolimus in second-line metastatic clear cell renal cell carcinoma (MARC-2 study)[J]. Cancers (Basel), 2021, 13(11): 2594. doi: 10.3390/cancers13112594
[59]	LE A,, COOPER C R,, GOUW A M, et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression[J]. Proc Natl Acad Sci USA, 2010, 107(5): 2037-2042. doi: 10.1073/pnas.0914433107
[60]	RAJESHKUMAR N V,, DUTTA P,, YABUUCHI S, et al. Therapeutic targeting of the Warburg effect in pancreatic cancer relies on an absence of p53 function[J]. Cancer Res, 2015, 75(16): 3355-3364. doi: 10.1158/0008-5472.CAN-15-0108
[61]	YU H Z,, YIN Y F,, YI Y F, et al. Targeting lactate dehydrogenase A (LDHA) exerts antileukemic effects on T-cell acute lymphoblastic leukemia[J]. Cancer Commun (Lond), 2020, 40(10): 501-517.
[62]	WEI R,, HACKMAN R M,, WANG Y F, et al. Targeting glycolysis with epigallocatechin-3-gallate enhances the efficacy of chemotherapeutics in pancreatic cancer cells and xenografts[J]. Cancers (Basel), 2019, 11(10): E1496.
[63]	WEI R,, MAO L M,, XU P, et al. Suppressing glucose metabolism with epigallocatechin-3-gallate (EGCG) reduces breast cancer cell growth in preclinical models[J]. Food Funct, 2018, 9(11): 5682-5696. doi: 10.1039/C8FO01397G
[64]	NONOMIYA Y,, NOGUCHI K,, KATAYAMA K, et al. Novel pharmacological effects of poly (ADP-ribose) polymerase inhibitor rucaparib on the lactate dehydrogenase pathway[J]. Biochem Biophys Res Commun, 2019, 510(4): 501-507. doi: 10.1016/j.bbrc.2019.01.133
[65]	FELMLEE M A,, JONES R S,, RODRIGUEZ-CRUZ V, et al. Monocarboxylate transporters (SLC16): function, regulation, and role in health and disease[J]. Pharmacol Rev, 2020, 72(2): 466-485. doi: 10.1124/pr.119.018762
[66]	GERLINGER M,, SANTOS C R,, SPENCER-DENE B, et al. Genome-wide RNA interference analysis of renal carcinoma survival regulators identifies MCT4 as a Warburg effect metabolic target[J]. J Pathol, 2012, 227(2): 146-156. doi: 10.1002/path.4006
[67]	SONVEAUX P,, COPETTI T,, DE SAEDELEER C J, et al. Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis[J]. PLoS One, 2012, 7(3): e33418. doi: 10.1371/journal.pone.0033418
[68]	GUO C,, HUANG T,, WANG Q H, et al. Monocarboxylate transporter 1 and monocarboxylate transporter 4 in cancer-endothelial co-culturing microenvironments promote proliferation, migration, and invasion of renal cancer cells[J]. Cancer Cell Int, 2019, 19: 170. doi: 10.1186/s12935-019-0889-8
[69]	BELOUECHE-BABARI M,, CASALS GALOBART T,, DELGADO-GONI T, et al. Monocarboxylate transporter 1 blockade with AZD3965 inhibits lipid biosynthesis and increases tumour immune cell infiltration[J]. Br J Cancer, 2020, 122(6): 895-903. doi: 10.1038/s41416-019-0717-x
[70]	HUANG T Y,, FENG Q,, WANG Z H, et al. Tumor-targeted inhibition of monocarboxylate transporter 1 improves T-cell immunotherapy of solid tumors[J]. Adv Healthc Mater, 2021, 10(4): e2000549.
[71]	PERTEGA-GOMES N,, FELISBINO S,, MASSIE C E, et al. A glycolytic phenotype is associated with prostate cancer progression and aggressiveness: a role for monocarboxylate transporters as metabolic targets for therapy[J]. J Pathol, 2015, 236(4): 517-530. doi: 10.1002/path.4547
[72]	FANG Y,, LIU W R,, TANG Z, et al. Monocarboxylate transporter 4 inhibition potentiates hepatocellular carcinoma immunotherapy through enhancing T cell infiltration and immune attack[J]. Hepatology, 2022.
[73]	KHAN Y,, SLATTERY T D,, PICKERING L M. Individualizing systemic therapies in first line treatment and beyond for advanced renal cell carcinoma[J]. Cancers, 2020, 12(12): 3750. doi: 10.3390/cancers12123750
[74]	ARAUJO L,, KHIM P,, MKHIKIAN H, et al. Glycolysis and glutaminolysis cooperatively control T cell function by limiting metabolite supply to N-glycosylation[J]. Elife, 2017, 6: e21330. doi: 10.7554/eLife.21330
[75]	KOUIDHI S,, BEN AYED F,, BENAMMAR ELGAAIED A. Targeting tumor metabolism: a new challenge to improve immunotherapy[J]. Front Immunol, 2018, 9: 353. doi: 10.3389/fimmu.2018.00353
[76]	CHEVRIER S,, LEVINE J H,, ZANOTELLI V R T, et al. An immune atlas of clear cell renal cell carcinoma[J]. Cell, 2017, 169(4): 736-749.e18. doi: 10.1016/j.cell.2017.04.016
[77]	COLEGIO O R,, CHU N Q,, SZABO A L, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid[J]. Nature, 2014, 513(7519): 559-563. doi: 10.1038/nature13490
[78]	ANGELIN A,, GIL-DE-GÓMEZ L,, DAHIYA S, et al. Foxp 3 reprograms T cell metabolism to function in low-glucose, high-lactate environments[J]. Cell Metab, 2017, 25(6): 1282-1293.e7. doi: 10.1016/j.cmet.2016.12.018
[79]	GINHOUX F,, SCHULTZE J L,, MURRAY P J, et al. New insights into the multidimensional concept of macrophage ontogeny, activation and function[J]. Nat Immunol, 2016, 17(1): 34-40. doi: 10.1038/ni.3324
[80]	TANAKA A,, SAKAGUCHI S. Regulatory T cells in cancer immunotherapy[J]. Cell Res, 2017, 27(1): 109-118. doi: 10.1038/cr.2016.151
[81]	SINGER K,, KASTENBERGER M,, GOTTFRIED E, et al. Warburg phenotype in renal cell carcinoma: high expression of glucose-transporter 1 (GLUT-1) correlates with low CD8(+) T-cell infiltration in the tumor[J]. Int J Cancer, 2011, 128(9): 2085-2095. doi: 10.1002/ijc.25543
[82]	SUKUMAR M,, LIU J,, JI Y, et al. Inhibiting glycolytic metabolism enhances CD8⁺ T cell memory and antitumor function[J]. J Clin Invest, 2013, 123(10): 4479-4488. doi: 10.1172/JCI69589
[83]	BECKERMANN K E,, HONGO R,, YE X, et al. CD 28 costimulation drives tumor-infiltrating T cell glycolysis to promote inflammation[J]. JCI Insight, 2020, 5(16): 138729.
[84]	PILON-THOMAS S,, KODUMUDI K N,, EL-KENAWI A E, et al. Neutralization of tumor acidity improves antitumor responses to immunotherapy[J]. Cancer Res, 2016, 76(6): 1381-1390. doi: 10.1158/0008-5472.CAN-15-1743
[85]	RENNER K,, BRUSS C,, SCHNELL A, et al. Restricting glycolysis preserves T cell effector functions and augments checkpoint therapy[J]. Cell Rep, 2019, 29(1): 135-150.e9. doi: 10.1016/j.celrep.2019.08.068
[86]	PATSOUKIS N,, BARDHAN K,, CHATTERJEE P, et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation[J]. Nat Commun, 2015, 6: 6692. doi: 10.1038/ncomms7692
[87]	CHEN S H,, NISHI M,, MORINE Y, et al. Epigallocatechin-3-gallate hinders metabolic coupling to suppress colorectal cancer malignancy through targeting aerobic glycolysis in cancer-associated fibroblasts[J]. Int J Oncol, 2022, 60(2): 19. doi: 10.3892/ijo.2022.5309
[88]	YU Y B,, LIANG Y,, LI D, et al. Glucose metabolism involved in PD-L1-mediated immune escape in the malignant kidney tumour microenvironment[J]. Cell Death Discov, 2021, 7(1): 15. doi: 10.1038/s41420-021-00401-7
[89]	YAKISICH J S,, AZAD N,, KAUSHIK V, et al. The biguanides metformin and buformin in combination with 2-deoxy-glucose or WZB-117 inhibit the viability of highly resistant human lung cancer cells[J]. Stem Cells Int, 2019, 2019: 6254269.
[90]	SAWAYAMA H,, OGATA Y,, ISHIMOTO T, et al. Glucose transporter 1 regulates the proliferation and cisplatin sensitivity of esophageal cancer[J]. Cancer Sci, 2019, 110(5): 1705-1714. doi: 10.1111/cas.13995
[91]	GONG Y,, JI P,, YANG Y S, et al. Metabolic-pathway-based subtyping of triple-negative breast cancer reveals potential therapeutic targets[J]. Cell Metab, 2021, 33(1): 51-64.e9. doi: 10.1016/j.cmet.2020.10.012
[92]	ZAPPASODI R,, SERGANOVA I,, COHEN I J, et al. CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours[J]. Nature, 2021, 591(7851): 652-658. doi: 10.1038/s41586-021-03326-4