nav emailalert searchbtn searchbox tablepage yinyongbenwen piczone journalimg journalInfo journalinfonormal searchdiv searchzone qikanlogo popupnotification paper paperNew
2026, 01, v.58 44-48
胃癌早期干预新靶点NAMPT-NAD+轴免疫逃逸调控机制及抑制剂应用前景
基金项目(Foundation): 国家自然科学基金(编号:82303426)
邮箱(Email): luguofang16@163.com;
DOI: 10.16096/J.cnki.nmgyxzz.2026.58.01.009
发布时间: 2026-01-31
出版时间: 2026-01-31
移动端阅读
摘要:

胃癌作为高发病率、高死亡率恶性肿瘤,存在早期诊断难、治疗手段有限的问题,且免疫检查点抑制剂(ICIs)在部分患者中应答率不高,亟需新治疗靶点与联合策略。烟酰胺磷酸核糖转移酶(NAMPT)作为烟酰胺腺嘌呤二核苷酸(NAD+)补救合成途径关键限速酶,在胃癌组织中高表达且与不良预后相关。本文综述显示,NAMPT-NAD+代谢轴是连接细胞代谢与肿瘤免疫的核心枢纽,其通过提升NAD+水平为肿瘤增殖供能,更可借助表观遗传修饰、信号通路调控(如经SIRT1介导IFN-γ/STAT1通路)上调PD-L1表达,抑制T细胞功能并构建免疫抑制性肿瘤微环境,从而调控胃癌免疫逃逸。此外,以FK866为代表的NAMPT抑制剂在胃癌临床前模型中展现抗肿瘤活性,但存在血小板减少症等毒性及药代动力学瓶颈。靶向NAMPT有望成为胃癌早期干预新策略,可探索单一疗法或与ICIs联合应用,但需解决新型高效低毒抑制剂开发、精准生物标志物筛选及复杂肿瘤微环境调控网络阐明等关键问题,为胃癌精准免疫治疗提供理论依据与研发方向。

Abstract:

KeyWords:
参考文献

[1] TOGASAKI K,SUKAWA Y,KANAI T,et al.Clinical Efficacy of Immune Checkpoint Inhibitors in the Treatment of Unresectable Advanced or Recurrent Gastric Cancer:An Evidence-based Review of Therapies[J].OncoTargets and Therapy,2018,32(11):8239—8250.

[2] KONO K,NAKAJIMA S,MIMURA K.Current Status of Immune Checkpoint Inhibitors for Gastric Cancer[J].Gastric Cancer,2020,23(4):565—578.

[3] FUCHS C S,DOI T,JANG R W,et al.Safety and Efficacy of Pembrolizumab Monotherapy in Patients with Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer:Phase 2 Clinical KEYNOTE-059 trial[J].JAMA Oncology,2018,4(5):e180013.

[4] LIU H,WANG F,LIANG J,et al.Targeting NAD Metabolism Regulates Extracellular Adenosine Levels to Improve the Cytotoxicity of CD8+ Effector T Cells in the Tumor Microenvironment of Gastric Cancer[J].Journal of Cancer Research and Clinical Oncology,2023,149(7):2743—2756.

[5] NAVAS L E,CARNERO A.NAD(+) Metabolism,Stemness,the Immune Response,and Cancer[J].Signal Transduction and Targeted Therapy,2021,6(1):2.

[6] LUCENA-CACACE A,OTERO-ALBIOL D,JIMENEZ-GARCIA M P,et al.NAMPT Overexpression Induces Cancer Stemness and Defines a Novel Tumor Signature for Glioma Prognosis[J].Oncotarget,2017,8(59):99 514—99 530.

[7] TAN B,YOUNG D A,LU Z,et al.Pharmacological Inhibition of Nicotinamide Phosphoribosyltransferase (NAMPT),An Enzyme Essential for NAD+ Biosynthesis,in Human Cancer Cells:Metabolic Basis and Potential Clinical Implications[J].Journal of Biological Chemistry,2013,288(5):3500—3511.

[8] TAN B,DONG S,SHEPARD R L,et al.Inhibition of Nicotinamide Phosphoribosyltransferase (NAMPT),An Enzyme Essential for NAD+ Biosynthesis,Leads to Altered Carbohydrate Metabolism in Cancer Cells[J].Journal of Biological Chemistry,2015,290(25):15 812—15 824.

[9] ZHANG W,REN H,CHEN W,et al.Nicotinamide Phosphoribosyltransferase in NAD(+) Metabolism:Physiological and Pathophysiological Implications[J].Cell Death Discovery,2025,11(1):371.

[10] GARTEN A,SCHUSTER S,PENKE M,et al.Physiological and Pathophysiological Roles of NAMPT and NAD Metabolism[J].Nature Reviews Endocrinology,2015,11(9):535—546.

[11] CANTó C,MENZIES K J,AUWERX J.NAD(+) Metabolism and the Control of Energy Homeostasis:A Balancing Act Between Mitochondria and the Nucleus[J].Cell Metabolism,2015,22(1):31—53.

[12] GHANEM M S,CAFFA I,MONACELLI F,et al.Inhibitors of NAD(+) Production in Cancer Treatment:State of the Art and Perspectives[J].International Journal of Molecular Sciences,2024,25(4):2092.

[13] BI T,CHE X,LIAO X,et al.Overexpression of Nampt in Gastric Cancer and Chemopotentiating Effects of the Nampt Inhibitor FK866 in Combination with Fluorouracil[J].Oncology Reports,2011,26(5):1251—1257.

[14] REDLER J,NELSON A E,HESKE C M.Mechanisms of Resistance to NAMPT Inhibitors in Cancer[J].Cancer Drug Resistance,2025,12(8):18.

[15] ZHAO W,CHEN R,ZHAO M,et al.High Glucose Promotes Gastric Cancer Chemoresistance in Vivo and in Vitro[J].Molecular Medicine Reports,2015,12(1):843—850.

[16] LAUBACH K,TURAN T,MATHEW R,et al.Tumor-intrinsic Metabolic Reprogramming and How it Drives Resistance to Anti-PD-1/PD-L1 Treatment[J].Cancer Drug Resistance,2023,6(3):611—641.

[17] KAR A,MEHROTRA S,CHATTERJEE S.CD38:T Cell Immuno-metabolic Modulator[J].Cells,2020,9(7):1716.

[18] LIN X,KANG K,CHEN P,et al.Regulatory Mechanisms of PD-1/PD-L1 in Cancers[J].Molecular Cancer,2024,23(1):108.

[19] GHANEM M S,MONACELLI F,NENCIONI A.Advances in NAD-lowering Agents for Cancer Treatment[J].Nutrients,2021,13(5):1665.

[20] YE T,HUANG H,CHEN K,et al.Development and Validation of Prognostic Signatures of NAD+ Metabolism and Immune-related Genes in Colorectal Cancer[J].Heliyon,2024,10(14):e34403.

[21] ZHANG F,LI Z,FANG F,et al.IRF1 Is A Core Transcriptional Regulatory Circuitry Member Promoting AML Progression by Regulating Lipid Metabolism[J].Experimental Hematology & Oncology,2025,14(1):25.

[22] LV H,LV G,CHEN C,et al.NAD(+) Metabolism Maintains Inducible PD-L1 Expression to Drive Tumor Immune Evasion[J].Cell Metabolism,2021,33(1):110—127.

[23] LUCENA-CACACE A,OTERO-ALBIOL D,JIMENEZ-GARCIA M P,et al.NAMPT Is A Potent onCogene in Colon Cancer Progression that Modulates Cancer Stem Cell Properties and Resistance to Therapy Through Sirt1 and PARP[J].Clinical Cancer Research,2018,24(5):1202—1215.

[24] AUDRITO V,MANAGO A,GAUDINO F,et al.NAD-biosynthetic and Consuming Enzymes as Central Players of Metabolic Regulation of Innate and Adaptive Immune Responses in Cancer[J].Frontiers in Immunology,2019,10(7):1720.

[25] NAVAS L E,CARNERO A.Nicotinamide Adenine Dinucleotide (NAD) Metabolism As A Relevant Target in Cancer[J].Cells,2022,11(17):2627.

[26] CHATTERJEE S,DAENTHANASANMAK A,CHAKRABORTY P,et al.CD38-NAD+ Axis Regulates Immunotherapeutic Anti-tumor T Cell Response[J].Cell Metabolism,2018,27(1):85—100.

[27] HASMANN M,SCHEMAINDA I.FK866,A Highly Specific Noncompetitive Inhibitor of Nicotinamide Phosphoribosyltransferase,Represents A Novel Mechanism for Induction of Tumor Cell Apoptosis[J].Cancer Research,2003,63(21):7436—7442.

[28] 陈锐,王展,黄寿奖.Nampt在胃癌组织中表达的临床意义及其与P-gp和Top-Ⅱα的相关性[J].现代肿瘤医学,2016,24(3):431—436.

[29] 何俊俐,沈贵月,刘安定,等.FK866对脓毒症小鼠肝损伤的保护作用[J].中华危重病急救医学,2018,30(6):583—587.

[30] MCKAY-CORKUM G B,COLLINS V J,YEUNG C,et al.Inhibition of NAD+-dependent Metabolic Processes Induce Cellular Necrosis and Tumor Regression in Rhabdomyosarcoma Models[J].Clinical Cancer Research,2023,29(21):4479—4491.

[31] 戴天明.抗癌先导化合物J020的临床前成药性研究[D].广州:华南理工大学,2019.

[32] YAKU K,OKABE K,HIKOSAKA K,et al.NAD Metabolism in Cancer Therapeutics[J].Frontiers in Oncology,2018,8(2):622.

[33] ROULSTON A,SHORE G C.New Strategies to Maximize Therapeutic Opportunities for NAMPT Inhibitors in Oncology[J].Molecular & Cellular Oncology,2016,3(1):e1052180.

[34] HOLEN K,SALTZ L B,HOLLYWOOD E,et al.The Pharmacokinetics,Toxicities,and Biologic Effects of FK866,A Nicotinamide Adenine Dinucleotide Biosynthesis Inhibitor[J].Investigational New Drugs,2008,26(1):45—51.

[35] PRAMONO A A,RATHER G M,HERMAN H,et al.NAD- and NADPH-contributing Enzymes As Therapeutic Targets in Cancer:An Overview[J].Biomolecules,2020,10(3):358.

基本信息:

DOI:10.16096/J.cnki.nmgyxzz.2026.58.01.009

中图分类号:R735.2

引用信息:

[1]杜瑞,芦国芳.胃癌早期干预新靶点NAMPT-NAD~+轴免疫逃逸调控机制及抑制剂应用前景[J].内蒙古医学杂志,2026,58(01):44-48.DOI:10.16096/J.cnki.nmgyxzz.2026.58.01.009.

基金信息:

国家自然科学基金(编号:82303426)

发布时间:

2026-01-31

出版时间:

2026-01-31

检 索 高级检索

引用

GB/T 7714-2015 格式引文
MLA格式引文
APA格式引文