New strategies for combined with immunotherapy of clear cell renal cell carcinoma: advances in aerobic glycolysis

Jiaqi SU; Wenhao XU; Xi TIAN; Aihetaimujiang ANWAIE; Yuanyuan QU; Guohai SHI; Hailiang ZHANG; Dingwei YE

doi:10.19401/j.cnki.1007-3639.2022.04.001

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New strategies for combined with immunotherapy of clear cell renal cell carcinoma: advances in aerobic glycolysis

Specialists' Commentary | 更新时间：2025-12-31

- New strategies for combined with immunotherapy of clear cell renal cell carcinoma: advances in aerobic glycolysis
- China Oncology Vol. 32, Issue 4, Pages: 287-297(2022)
- 作者机构：
  
  复旦大学附属肿瘤医院泌尿外科,复旦大学上海医学院肿瘤学系,上海 200032
- 作者简介：
- 基金信息：
- DOI：10.19401/j.cnki.1007-3639.2022.04.001
  CLC： R737.11
- Received：29 August 2021，
  
  Revised：2021-03-03，
  
  Published：30 April 2022
- 稿件说明：
移动端阅览
Jiaqi SU, Wenhao XU, Xi TIAN, et al. New strategies for combined with immunotherapy of clear cell renal cell carcinoma: advances in aerobic glycolysis[J]. China Oncology, 2022, 32(4): 287-297.
DOI：

Jiaqi SU, Wenhao XU, Xi TIAN, et al. New strategies for combined with immunotherapy of clear cell renal cell carcinoma: advances in aerobic glycolysis[J]. China Oncology, 2022, 32(4): 287-297. DOI： 10.19401/j.cnki.1007-3639.2022.04.001.

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。

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.

关键词

Keywords

references

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 http://doi.org/10.1016/j.ejca.2018.07.005 https://linkinghub.elsevier.com/retrieve/pii/S0959804918309559 https://linkinghub.elsevier.com/retrieve/pii/S0959804918309559

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 http://doi.org/10.3322/caac.21590 https://onlinelibrary.wiley.com/doi/abs/10.3322/caac.21590 https://onlinelibrary.wiley.com/doi/abs/10.3322/caac.21590

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 http://doi.org/10.3322/caac.21660 https://onlinelibrary.wiley.com/doi/10.3322/caac.21660 https://onlinelibrary.wiley.com/doi/10.3322/caac.21660

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 http://doi.org/10.3322/caac.21654 https://onlinelibrary.wiley.com/doi/10.3322/caac.21654 https://onlinelibrary.wiley.com/doi/10.3322/caac.21654

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 http://doi.org/10.1016/j.eururo.2016.02.029 https://linkinghub.elsevier.com/retrieve/pii/S0302283816002062 https://linkinghub.elsevier.com/retrieve/pii/S0302283816002062

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 http://doi.org/10.1111/j.1464-410X.2008.08259.x https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2008.08259.x https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2008.08259.x

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 http://doi.org/10.1016/j.juro.2009.12.035 http://www.jurology.com/doi/10.1016/j.juro.2009.12.035 http://www.jurology.com/doi/10.1016/j.juro.2009.12.035

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 http://doi.org/10.1016/j.juro.2012.04.006 http://www.jurology.com/doi/10.1016/j.juro.2012.04.006 http://www.jurology.com/doi/10.1016/j.juro.2012.04.006

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.

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 http://doi.org/10.1016/j.cell.2011.02.013 https://linkinghub.elsevier.com/retrieve/pii/S0092867411001279 https://linkinghub.elsevier.com/retrieve/pii/S0092867411001279

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 http://doi.org/10.1016/j.ccell.2015.12.004 https://linkinghub.elsevier.com/retrieve/pii/S1535610815004687 https://linkinghub.elsevier.com/retrieve/pii/S1535610815004687

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 http://doi.org/10.1016/j.cmet.2015.12.006 https://linkinghub.elsevier.com/retrieve/pii/S155041311500621X https://linkinghub.elsevier.com/retrieve/pii/S155041311500621X

WARBURG O . On the origin of cancer cells [J ] . Science , 1956 , 123 ( 3191 ): 309 - 314 . DOI: 10.1126/science.123.3191.309 http://doi.org/10.1126/science.123.3191.309

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 http://doi.org/10.1371/journal.pgen.1002312 https://dx.plos.org/10.1371/journal.pgen.1002312 https://dx.plos.org/10.1371/journal.pgen.1002312

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 http://doi.org/10.1016/j.apsb.2015.05.007 https://linkinghub.elsevier.com/retrieve/pii/S2211383515000817 https://linkinghub.elsevier.com/retrieve/pii/S2211383515000817

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 http://doi.org/10.1158/0008-5472.CAN-15-1859 http://cancerres.aacrjournals.org/lookup/doi/10.1158/0008-5472.CAN-15-1859 http://cancerres.aacrjournals.org/lookup/doi/10.1158/0008-5472.CAN-15-1859

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 http://doi.org/10.1038/nature12222 https://doi.org/10.1038/nature12222 https://doi.org/10.1038/nature12222

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 http://doi.org/10.1016/j.cell.2019.12.026 https://linkinghub.elsevier.com/retrieve/pii/S0092867419313881 https://linkinghub.elsevier.com/retrieve/pii/S0092867419313881

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 http://doi.org/10.1016/j.cmet.2018.07.020 https://linkinghub.elsevier.com/retrieve/pii/S1550413118304637 https://linkinghub.elsevier.com/retrieve/pii/S1550413118304637

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 .

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 http://doi.org/10.1111/j.1464-410X.2007.06765.x https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2007.06765.x https://onlinelibrary.wiley.com/doi/10.1111/j.1464-410X.2007.06765.x

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 http://doi.org/10.1007/s11255-019-02372-2 https://doi.org/10.1007/s11255-019-02372-2 https://doi.org/10.1007/s11255-019-02372-2

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 http://doi.org/10.1038/bjc.2013.173 https://doi.org/10.1038/bjc.2013.173 https://doi.org/10.1038/bjc.2013.173

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 http://doi.org/10.1038/s41598-020-63232-z https://doi.org/10.1038/s41598-020-63232-z https://doi.org/10.1038/s41598-020-63232-z

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 http://doi.org/10.1016/j.jfda.2017.03.009 https://linkinghub.elsevier.com/retrieve/pii/S1021949817300856 https://linkinghub.elsevier.com/retrieve/pii/S1021949817300856

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 .

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 http://doi.org/10.1002/cmdc.201600276 https://onlinelibrary.wiley.com/doi/10.1002/cmdc.201600276 https://onlinelibrary.wiley.com/doi/10.1002/cmdc.201600276

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 http://doi.org/10.1016/j.phymed.2018.09.003 https://linkinghub.elsevier.com/retrieve/pii/S0944711318302848 https://linkinghub.elsevier.com/retrieve/pii/S0944711318302848

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 http://doi.org/10.1038/s41557-018-0132-6 https://doi.org/10.1038/s41557-018-0132-6 https://doi.org/10.1038/s41557-018-0132-6

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 http://doi.org/10.1002/anie.201905578 https://onlinelibrary.wiley.com/doi/10.1002/anie.201905578 https://onlinelibrary.wiley.com/doi/10.1002/anie.201905578

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 http://doi.org/10.1111/cas.12280 https://onlinelibrary.wiley.com/doi/10.1111/cas.12280 https://onlinelibrary.wiley.com/doi/10.1111/cas.12280

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 http://doi.org/10.1007/s00432-020-03278-8 https://doi.org/10.1007/s00432-020-03278-8 https://doi.org/10.1007/s00432-020-03278-8

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 http://doi.org/10.1016/j.ccr.2013.06.014 https://linkinghub.elsevier.com/retrieve/pii/S1535610813002882 https://linkinghub.elsevier.com/retrieve/pii/S1535610813002882

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 .

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 http://doi.org/10.7150/ijbs.58295 https://www.ijbs.com/v17p2205.htm https://www.ijbs.com/v17p2205.htm

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 http://doi.org/10.1038/cddis.2014.545 https://doi.org/10.1038/cddis.2014.545 https://doi.org/10.1038/cddis.2014.545

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 .

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 .

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 http://doi.org/10.1021/acs.nanolett.1c03089 https://pubs.acs.org/doi/10.1021/acs.nanolett.1c03089 https://pubs.acs.org/doi/10.1021/acs.nanolett.1c03089

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 http://doi.org/10.1186/s13046-017-0530-4 http://jeccr.biomedcentral.com/articles/10.1186/s13046-017-0530-4 http://jeccr.biomedcentral.com/articles/10.1186/s13046-017-0530-4

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 http://doi.org/10.1016/j.phrs.2020.105367 https://linkinghub.elsevier.com/retrieve/pii/S1043661820316753 https://linkinghub.elsevier.com/retrieve/pii/S1043661820316753

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 http://doi.org/10.1186/s12885-022-09183-2 https://doi.org/10.1186/s12885-022-09183-2 https://doi.org/10.1186/s12885-022-09183-2

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 http://doi.org/10.1158/1535-7163.MCT-07-0482 http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT-07-0482 http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT-07-0482

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 http://doi.org/10.1158/1535-7163.MCT-13-0097 http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT-13-0097 http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT-13-0097

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 http://doi.org/10.1002/ijc.31868 https://onlinelibrary.wiley.com/doi/10.1002/ijc.31868 https://onlinelibrary.wiley.com/doi/10.1002/ijc.31868

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 http://doi.org/10.1038/s41467-018-06287-x https://doi.org/10.1038/s41467-018-06287-x https://doi.org/10.1038/s41467-018-06287-x

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 .

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 .

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 http://doi.org/10.1371/journal.pbio.3001197 https://dx.plos.org/10.1371/journal.pbio.3001197 https://dx.plos.org/10.1371/journal.pbio.3001197

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 http://doi.org/10.1038/onc.2011.137 https://doi.org/10.1038/onc.2011.137 https://doi.org/10.1038/onc.2011.137

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 http://doi.org/10.1002/cam4.1748 https://onlinelibrary.wiley.com/doi/10.1002/cam4.1748 https://onlinelibrary.wiley.com/doi/10.1002/cam4.1748

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.

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 http://doi.org/10.1002/ijc.32756 https://onlinelibrary.wiley.com/doi/10.1002/ijc.32756 https://onlinelibrary.wiley.com/doi/10.1002/ijc.32756

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 http://doi.org/10.3389/fonc.2020.00159 https://www.frontiersin.org/article/10.3389/fonc.2020.00159/full https://www.frontiersin.org/article/10.3389/fonc.2020.00159/full

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 http://doi.org/10.1038/nchembio.1060 https://doi.org/10.1038/nchembio.1060 https://doi.org/10.1038/nchembio.1060

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 .

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 http://doi.org/10.1159/000445125 https://www.karger.com/Article/FullText/445125 https://www.karger.com/Article/FullText/445125

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 http://doi.org/10.3390/cancers13112594 https://www.mdpi.com/2072-6694/13/11/2594 https://www.mdpi.com/2072-6694/13/11/2594

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 http://doi.org/10.1073/pnas.0914433107 https://pnas.org/doi/full/10.1073/pnas.0914433107 https://pnas.org/doi/full/10.1073/pnas.0914433107

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 http://doi.org/10.1158/0008-5472.CAN-15-0108 http://cancerres.aacrjournals.org/lookup/doi/10.1158/0008-5472.CAN-15-0108 http://cancerres.aacrjournals.org/lookup/doi/10.1158/0008-5472.CAN-15-0108

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 .

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 .

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 http://doi.org/10.1039/C8FO01397G http://xlink.rsc.org/?DOI=C8FO01397G http://xlink.rsc.org/?DOI=C8FO01397G

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 http://doi.org/10.1016/j.bbrc.2019.01.133 https://linkinghub.elsevier.com/retrieve/pii/S0006291X19301615 https://linkinghub.elsevier.com/retrieve/pii/S0006291X19301615

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 http://doi.org/10.1124/pr.119.018762 http://pharmrev.aspetjournals.org/lookup/doi/10.1124/pr.119.018762 http://pharmrev.aspetjournals.org/lookup/doi/10.1124/pr.119.018762

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 http://doi.org/10.1002/path.4006 https://onlinelibrary.wiley.com/doi/10.1002/path.4006 https://onlinelibrary.wiley.com/doi/10.1002/path.4006

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 http://doi.org/10.1371/journal.pone.0033418 https://dx.plos.org/10.1371/journal.pone.0033418 https://dx.plos.org/10.1371/journal.pone.0033418

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 http://doi.org/10.1186/s12935-019-0889-8 https://doi.org/10.1186/s12935-019-0889-8 https://doi.org/10.1186/s12935-019-0889-8

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 http://doi.org/10.1038/s41416-019-0717-x https://doi.org/10.1038/s41416-019-0717-x https://doi.org/10.1038/s41416-019-0717-x

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.

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 http://doi.org/10.1002/path.4547 https://onlinelibrary.wiley.com/doi/10.1002/path.4547 https://onlinelibrary.wiley.com/doi/10.1002/path.4547

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 .

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 http://doi.org/10.3390/cancers12123750 https://www.mdpi.com/2072-6694/12/12/3750 https://www.mdpi.com/2072-6694/12/12/3750

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 http://doi.org/10.7554/eLife.21330 https://elifesciences.org/articles/21330 https://elifesciences.org/articles/21330

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 http://doi.org/10.3389/fimmu.2018.00353 http://journal.frontiersin.org/article/10.3389/fimmu.2018.00353/full http://journal.frontiersin.org/article/10.3389/fimmu.2018.00353/full

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 http://doi.org/10.1016/j.cell.2017.04.016 https://linkinghub.elsevier.com/retrieve/pii/S0092867417304294 https://linkinghub.elsevier.com/retrieve/pii/S0092867417304294

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 http://doi.org/10.1038/nature13490 https://doi.org/10.1038/nature13490 https://doi.org/10.1038/nature13490

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 http://doi.org/10.1016/j.cmet.2016.12.018 https://linkinghub.elsevier.com/retrieve/pii/S1550413116306519 https://linkinghub.elsevier.com/retrieve/pii/S1550413116306519

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 http://doi.org/10.1038/ni.3324 https://doi.org/10.1038/ni.3324 https://doi.org/10.1038/ni.3324

TANAKA A , SAKAGUCHI S . Regulatory T cells in cancer immunotherapy [J ] . Cell Res , 2017 , 27 ( 1 ): 109 - 118 . DOI: 10.1038/cr.2016.151 http://doi.org/10.1038/cr.2016.151 https://doi.org/10.1038/cr.2016.151 https://doi.org/10.1038/cr.2016.151

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 http://doi.org/10.1002/ijc.25543 https://onlinelibrary.wiley.com/doi/10.1002/ijc.25543 https://onlinelibrary.wiley.com/doi/10.1002/ijc.25543

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 http://doi.org/10.1172/JCI69589 http://www.jci.org/articles/view/69589 http://www.jci.org/articles/view/69589

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 .

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 http://doi.org/10.1158/0008-5472.CAN-15-1743 http://cancerres.aacrjournals.org/lookup/doi/10.1158/0008-5472.CAN-15-1743 http://cancerres.aacrjournals.org/lookup/doi/10.1158/0008-5472.CAN-15-1743

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 http://doi.org/10.1016/j.celrep.2019.08.068 https://linkinghub.elsevier.com/retrieve/pii/S2211124719311234 https://linkinghub.elsevier.com/retrieve/pii/S2211124719311234

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 http://doi.org/10.1038/ncomms7692 https://doi.org/10.1038/ncomms7692 https://doi.org/10.1038/ncomms7692

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 http://doi.org/10.3892/ijo.2022.5309 http://www.spandidos-publications.com/10.3892/ijo.2022.5309 http://www.spandidos-publications.com/10.3892/ijo.2022.5309

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 http://doi.org/10.1038/s41420-021-00401-7 https://doi.org/10.1038/s41420-021-00401-7 https://doi.org/10.1038/s41420-021-00401-7

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 .

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 http://doi.org/10.1111/cas.13995 https://onlinelibrary.wiley.com/doi/10.1111/cas.13995 https://onlinelibrary.wiley.com/doi/10.1111/cas.13995

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 http://doi.org/10.1016/j.cmet.2020.10.012 https://linkinghub.elsevier.com/retrieve/pii/S1550413120305453 https://linkinghub.elsevier.com/retrieve/pii/S1550413120305453

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 http://doi.org/10.1038/s41586-021-03326-4 https://doi.org/10.1038/s41586-021-03326-4 https://doi.org/10.1038/s41586-021-03326-4

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