切换至 "中华医学电子期刊资源库"

中华普通外科学文献(电子版) ›› 2025, Vol. 19 ›› Issue (02) : 124 -129. doi: 10.3877/cma.j.issn.1674-0793.2025.02.011

综述

代谢功能障碍与免疫微环境关系在肝细胞癌发生发展的作用机制
张大山1, 李贺鹏1, 蒋福林1, 商中华1,()   
  1. 1. 030001 太原,山西医科大学第二医院普通外科
  • 收稿日期:2024-11-10 出版日期:2025-04-01
  • 通信作者: 商中华

Mechanisms of the relationship between metabolic dysfunction and immune microenvironment in the occurrence and development of hepatocellular carcinoma

Dashan Zhang1, Hepeng Li1, Fulin Jiang1, Zhonghua Shang1,()   

  1. 1. Department of General Surgery, the Second Hospital of Shanxi Medical University, Taiyuan 030001, China
  • Received:2024-11-10 Published:2025-04-01
  • Corresponding author: Zhonghua Shang
引用本文:

张大山, 李贺鹏, 蒋福林, 商中华. 代谢功能障碍与免疫微环境关系在肝细胞癌发生发展的作用机制[J/OL]. 中华普通外科学文献(电子版), 2025, 19(02): 124-129.

Dashan Zhang, Hepeng Li, Fulin Jiang, Zhonghua Shang. Mechanisms of the relationship between metabolic dysfunction and immune microenvironment in the occurrence and development of hepatocellular carcinoma[J/OL]. Chinese Archives of General Surgery(Electronic Edition), 2025, 19(02): 124-129.

肝细胞癌(HCC)是最常见的原发性肝脏恶性肿瘤,其复杂的发病机制一直是研究的热点。随着代谢功能障碍与肿瘤免疫微环境相互作用的深入探索,越来越多的证据表明两者在肿瘤演进、免疫逃逸以及免疫治疗反应中发挥着关键作用。代谢功能障碍涉及糖酵解、氨基酸代谢等多种生化过程,在肿瘤细胞中常常发生代谢异常,以满足其快速生长和增殖的能量与物质需求,也影响了肿瘤微环境中的免疫细胞功能,从而影响其免疫应答和抗肿瘤活性。近年来,多项报道揭示了代谢功能障碍在调控HCC免疫微环境中的免疫细胞功能、免疫逃逸机制及抗肿瘤免疫反应中的重要性,但对于其如何影响免疫微环境的细胞成分及其功能,仍缺乏系统性的综述与深入分析。本研究总结代谢功能障碍与HCC免疫微环境相互作用的最新研究进展,并探讨其在免疫治疗中的潜在应用,提出可能的代谢靶点,为HCC提供了新的治疗方向和思路。

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver, and its complex pathogenesis has been the focus of researches. With the in-depth exploration of the interaction between metabolic dysfunction and tumor immune microenvironment, there is increasing evidence that they play a key role in tumor evolution, immune escape, and immunotherapy response.Metabolic dysfunction involves a variety of biochemical processes such as glycolysis, amino acid metabolism,which are often abnormal in tumor cells to meet the energy and material requirements of rapid growth and proliferation. At the same time, these metabolic abnormalities also affect immune cells in the tumor microenvironment, thus affecting their immune response and anti-tumor activity. In recent years, a number of reports have revealed the importance of metabolic dysfunction in regulating immune cell function, immune escape mechanism and anti-tumor immune response in the immune microenvironment of HCC. However,there is still lack of systematic review and in-depth analysis of how metabolic dysfunction affecting the cellular components and functions of the HCC immune microenvironment. This study summarizes the latest research progress on the interaction between metabolic dysfunction and HCC immune microenvironment,explores its potential application in immunotherapy, proposes possible metabolic targets, and provides new directions and ideas for future HCC treatment.

[1]
Foglia B, Beltrà M, Sutti S, et al. Metabolic reprogramming of HCC: A new microenvironment for immune responses[J]. Int J Mol Sci, 2023, 24(8): 7463.
[2]
Bhat N, Mani A. Dysregulation of lipid and glucose metabolism in nonalcoholic fatty liver disease[J]. Nutrients, 2023, 15(10): 2323.
[3]
Cheng Y, He J, Zuo B, et al. Role of lipid metabolism in hepatocellular carcinoma[J]. Discov Oncol, 2024, 15(1): 206.
[4]
Mooli RGR, Ramakrishnan SK. Liver steatosis is a driving factor of inflammation[J]. Cell Mol Gastroenterol Hepatol, 2022, 13(4):1267-1270.
[5]
Bhat SA, Farooq Z, Ismail H, et al. Unraveling the sweet secrets of HCC: glucometabolic rewiring in hepatocellular carcinoma[J].Technol Cancer Res Treat, 2023, 22: 15330338231219434.
[6]
Feng J, Li J, Wu L, et al. Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma[J]. J Exp Clin Cancer Res, 2020, 39(1): 126.
[7]
Zhang X, Song W, Gao Y, et al. The role of tumor metabolic reprogramming in tumor immunity[J]. Int J Mol Sci, 2023, 24(24):17422.
[8]
Liu Y, Hao C, Li L, et al. The role of oxidative stress in the development and therapeutic intervention of hepatocellular carcinoma[J]. Curr Cancer Drug Targets, 2023, 23(10): 792-804.
[9]
Čipak Gašparović A. Free radical research in cancer[J].Antioxidants (Basel), 2020, 9(2): 157.
[10]
Wang L, Zhang L. Protein kinase N2 reduces hydrogen peroxideinduced damage and apoptosis in PC12 cells by antioxidative stress and activation of the mTOR pathway[J]. Evid Based Complement Alternat Med, 2022, 2022: 2483669.
[11]
Shiau JP, Chuang YT, Tang JY, et al. The impact of oxidative stress and AKT pathway on cancer cell functions and its application to natural products[J]. Antioxidants (Basel), 2022, 11(9): 1845.
[12]
Ramos-Lopez O, Riezu-Boj JI, Milagro FI, et al. Association of methylation signatures at hepatocellular carcinoma pathway genes with adiposity and insulin resistance phenotypes[J]. Nutr Cancer,2019, 71(5): 840-851.
[13]
Zhang YT, Xing ML, Fang HH, et al. Effects of lactate on metabolism and differentiation of CD4(+) T cells[J]. Mol Immunol,2023, 154: 96-107.
[14]
Peng X, He Z, Yuan D, et al. Lactic acid: the culprit behind the immunosuppressive microenvironment in hepatocellular carcinoma[J]. Biochim Biophys Acta Rev Cancer, 2024, 1879(5):189164.
[15]
Worsley CM, Veale RB, Mayne ES. The acidic tumour microenvironment: manipulating the immune response to elicit escape[J]. Hum Immunol, 2022, 83(5): 399-408.
[16]
Miao T, Nan Y. Hepatocellular carcinoma immune microenvironment[J]. Zhonghua Gan Zang Bing Za Zhi, 2022,30(9): 923-930.
[17]
Vanderborght B, De Muynck K, Gijbels E, et al. Transient Kupffer cell depletion and subsequent replacement by infiltrating monocyte-derived cells does not alter the induction or progression of hepatocellular carcinoma[J]. Int J Cancer, 2023, 152(12): 2615-2628.
[18]
Manoharan I, Prasad PD, Thangaraju M, et al. Lactatedependent regulation of immune responses by dendritic cells and macrophages[J]. Front Immunol, 2021, 12: 691134.
[19]
Huang J, Wu Q, Geller DA, et al. Macrophage metabolism,phenotype, function, and therapy in hepatocellular carcinoma(HCC)[J]. J Transl Med, 2023, 21(1): 815.
[20]
Thangaraj JL, Coffey M, Lopez E, et al. Disruption of TGF-β signaling pathway is required to mediate effective killing of hepatocellular carcinoma by human iPSC-derived NK cells[J]. Cell Stem Cell, 2024, 31(9): 1327-1343, e1325.
[21]
Ge Z, Wu S, Zhang Z, et al. Mechanism of tumor cells escaping from immune surveillance of NK cells[J]. Immunopharmacol Immunotoxicol, 2020, 42(3): 187-198.
[22]
Wang F, Liu L, Wang J, et al. Gain-of-function of IDO in DCs inhibits T cell immunity by metabolically regulating surface molecules and cytokines[J]. Exp Ther Med, 2023, 25(5): 234.
[23]
Chen Z, Yu M, Zhang B, et al. SIGLEC15, negatively correlated with PD-L1 in HCC, could induce CD8+ T cell apoptosis to promote immune evasion[J]. Oncoimmunology, 2024, 13(1):2376264.
[24]
Hou K, Xu X, Ge X, et al. Blockade of PD-1 and CTLA-4: A potent immunotherapeutic approach for hepatocellular carcinoma[J]. Biofactors, 2024, 50(2): 250-265.
[25]
Jedlička M, Feglarová T, Janstová L, et al. Lactate from the tumor microenvironment - A key obstacle in NK cell-based immunotherapies[J]. Front Immunol, 2022, 13: 932055.
[26]
Sanmarco LM, Rone JM, Polonio CM, et al. Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells[J]. Nature,2023, 620(7975): 881-889.
[27]
Chen IC, Awasthi D, Hsu CL, et al. High-fat diet-induced obesity alters dendritic cell homeostasis by enhancing mitochondrial fatty acid oxidation[J]. J Immunol, 2022, 209(1): 69-76.
[28]
Prasad YR, Anakha J, Pande AH. Treating liver cancer through arginine depletion[J]. Drug Discov Today, 2024, 29(4): 103940.
[29]
Zhu GQ, Tang Z, Huang R, et al. CD36(+) cancer-associated fibroblasts provide immunosuppressive microenvironment for hepatocellular carcinoma via secretion of macrophage migration inhibitory factor[J]. Cell Discov, 2023, 9(1): 25.
[30]
Yin Y, Feng W, Chen J, et al. Immunosuppressive tumor microenvironment in the progression, metastasis, and therapy of hepatocellular carcinoma: from bench to bedside[J]. Exp Hematol Oncol, 2024, 13(1): 72.
[31]
Khanam A, Kottilil S. New therapeutics for HCC: does tumor immune microenvironment matter?[J]. Int J Mol Sci, 2022, 24(1):437.
[32]
Hayes C, Donohoe CL, Davern M, et al. The oncogenic and clinical implications of lactate induced immunosuppression in the tumour microenvironment[J]. Cancer Lett, 2021, 500: 75-86.
[33]
Teng Y, Xu L, Li W, et al. Targeting reactive oxygen species and fat acid oxidation for the modulation of tumor-associated macrophages: A narrative review[J]. Front Immunol, 2023, 14:1224443.
[34]
Arconzo M, Piccinin E, Pasculli E, et al. Hepatic-specific Pgc-1α ablation drives fibrosis in a MASH model[J]. Liver Int, 2024,44(10): 2738-2752.
[35]
Bansal SK, Bansal MB. Pathogenesis of MASLD and MASH - role of insulin resistance and lipotoxicity[J]. Aliment Pharmacol Ther,2024, 59 Suppl 1: S10-S22.
[36]
Mauricio D, Escalada J, Pérez A, et al. Metabolic dysfunctionassociated steatohepatitis (MASLD) and metabolic dysfunctionassociated steatohepatitis (MASH) require urgent attention by primary care physicians and endocrinologists[J]. Endocrinol Diabetes Nutr (Engl Ed), 2024, 71(4): 149-151.
[37]
Tiku V, Kew C, Kofoed EM, et al. Acinetobacter baumannii secretes a bioactive lipid that triggers inflammatory signaling and cell death[J]. Front Microbiol, 2022, 13: 870101.
[38]
Khoury M, Guo Q, Furuta K, et al. Glycogen synthase kinase 3 activity enhances liver inflammation in MASH[J]. JHEP Rep,2024, 6(6): 101073.
[39]
Xu GX, Wei S, Yu C, et al. Activation of Kupffer cells in NAFLD and NASH: mechanisms and therapeutic interventions[J]. Front Cell Dev Biol, 2023, 11: 1199519.
[40]
Papachristoforou E, Ramachandran P. Macrophages as key regulators of liver health and disease[J]. Int Rev Cell Mol Biol,2022, 368: 143-212.
[41]
Highton AJ, Schuster IS, Degli-Esposti MA, et al. The role of natural killer cells in liver inflammation[J]. Semin Immunopathol,2021, 43(4): 519-533.
[42]
Westenberger G, Sellers J, Fernando S, et al. Function of mitogenactivated protein kinases in hepatic inflammation[J]. J Cell Signal,2021, 2(3): 172-180.
[43]
Borde S, Matosevic S. Metabolic adaptation of NK cell activity and behavior in tumors: challenges and therapeutic opportunities[J].Trends Pharmacol Sci, 2023, 44(11): 832-848.
[44]
Zhao M, Yuan H, Yang G, et al. Tumour cell-expressed PDL1 reprograms lipid metabolism via EGFR/ITGB4/SREBP1c signalling in liver cancer[J]. JHEP Rep, 2024, 6(4): 101009.
[45]
Wang H, Tsung A, Mishra L, et al. Regulatory T cell: A doubleedged sword from metabolic-dysfunction-associated steatohepatitis to hepatocellular carcinoma[J]. EBioMedicine, 2024, 101: 105031.
[46]
Singh S, Karthikeyan C, Moorthy N. Recent advances in the development of fatty acid synthase inhibitors as anticancer agents[J]. Mini Rev Med Chem, 2020, 20(18): 1820-1837.
[47]
Wong SK, Beckermann KE, Johnson DB, et al. Combining anticytotoxic T-lymphocyte antigen 4 (CTLA-4) and -programmed cell death protein 1 (PD-1) agents for cancer immunotherapy[J].Expert Opin Biol Ther, 2021, 21(12): 1623-1634.
[48]
Wang L, Cao ZM, Zhang LL, et al. The role of gut microbiota in some liver diseases: from an immunological perspective[J]. Front Immunol, 2022, 13: 923599.
[49]
Xie Y, Liu F. The role of the gut microbiota in tumor, immunity,and immunotherapy[J]. Front Immunol, 2024, 15: 1410928.
[50]
Aderinto N, Abdulbasit MO, Tangmi ADE, et al. Unveiling the growing significance of metabolism in modulating immune cell function: exploring mechanisms and implications; a review[J]. Ann Med Surg (Lond), 2023, 85(11): 5511-5522.
[51]
Li H, He Q, Zhou GM, et al. Potential biomarkers for the prognosis and treatment of HCC immunotherapy[J]. Eur Rev Med Pharmacol Sci, 2023, 27(5): 2027-2046.
[52]
Xu FQ, Dong MM, Wang ZF, et al. Metabolic rearrangements and intratumoral heterogeneity for immune response in hepatocellular carcinoma[J]. Front Immunol, 2023, 14: 1083069.
[53]
Bao M, Wu A. Understanding the heterogeneity in liver hepatocellular carcinoma with a special focus on malignant cell through single-cell analysis[J]. Discov Oncol, 2024, 15(1): 241.
[54]
Yang Y, Sun L, Chen Z, et al. The immune-metabolic crosstalk between CD3(+)C1q(+)TAM and CD8(+)T cells associated with relapse-free survival in HCC[J]. Front Immunol, 2023, 14:1033497.
[1] 钱小梅, 罗洪, 李智慧, 周代君, 李东. 76例乙型肝炎肝硬化并发原发性肝癌的高危因素Logistic分析[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(03): 251-253.
[2] 卢超, 陈波, 邢志祥, 周鹏, 王帅. 不同入路下腹腔镜解剖性肝脏切除术治疗肝细胞癌的临床对比[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(03): 254-257.
[3] 张小松, 马俊永, 李锡锋, 施乐华, 沈锋. 腹腔镜鞘内解剖性右半肝切除联合区域淋巴结清扫[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(03): 245-245.
[4] 马海龙, 吴少锋, 王茂, 陈学锋, 代引海. 腹腔镜近端胃切除不同消化道重建围手术期安全性及抗反流效果研究[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(03): 274-277.
[5] 李鹏, 刘光世, 李涛. 基于黑色素瘤相关抗原A6在胃癌转移与预后的作用机制研究[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(03): 282-284.
[6] 施浩, 冯晨明, 解曙哲, 刘俊杰, 赵强, 韩超. 胸腹腔镜联合食管残胃胸内吻合治疗SiewertⅡ型食管胃结合部腺癌的近期疗效分析[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(03): 290-293.
[7] 徐伯群, 单留群, 高志慧. 进展期右半结肠癌CME+D3根治术中不同淋巴结清扫范围的临床研究[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(03): 309-312.
[8] 赵敏, 韩加刚. 保留左结肠动脉的腹腔镜直肠癌根治术的临床效果观察[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(03): 313-316.
[9] 袁强, 张华宇, 闫璋哲, 朱含放, 陈光, 孙亮, 吕远, 陈纲, 赵锁. cN0峡部偏侧甲状腺乳头状癌中央区淋巴结转移的术前预测模型[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(03): 333-336.
[10] 朱宗恒, 张志火. 甲状腺乳头状癌对侧中央区淋巴结转移的危险因素分析及预测模型构建[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(03): 337-340.
[11] 李云龙, 夏旭良, 刘伟, 江志强, 唐立, 刘凯, 刘昊中, 张思远. 微波消融与TOET治疗T1N0M0期甲状腺乳头状癌的效果比较[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(03): 341-344.
[12] 杨娜, 胡刚, 潘越. 保乳术和改良根治术后行新辅助化疗对三阴性乳腺癌血清标志物影响[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(03): 345-348.
[13] 董家旭, 宋美姿, 毕讯. 射频消融术联合TSH抑制治疗甲状腺微小乳头状癌的效果及生存预后分析[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(02): 200-203.
[14] 王奇, 李林峰, 林启盛, 龚朝阳, 连文清, 龙永富, 黄亚强. 广东省医学会泌尿外科疑难病例多学科会诊(第23期)——VHL综合征并双侧肾细胞癌[J/OL]. 中华腔镜泌尿外科杂志(电子版), 2025, 19(02): 272-277.
[15] 朱锴, 李爽, 刘艳成, 张净宇, 张宏, 张洪亮, 刘金伟, 胡永成. 肾癌脊柱转移瘤手术疗效及预后因素分析报道:附系统综述[J/OL]. 中华老年骨科与康复电子杂志, 2025, 11(02): 87-101.
阅读次数
全文


摘要