AbstractThe primary impediment to the success of immunotherapy lies in the immune evasion orchestrated by tumors, contributing to the suboptimal overall response rates observed. Despite this recognition, the intricacies of the underlying mechanisms remain incompletely understood. Through preliminary detection of clinical patient tissues, we have found that ALDH1A1 was a key gene for the prognosis of cancer patients and tumor glycolysis.

摘要免疫治疗成功的主要障碍在于肿瘤引起的免疫逃避，导致观察到的总体反应率不理想。尽管有这种认识，但潜在机制的复杂性仍未完全了解。通过对临床患者组织的初步检测，我们发现ALDH1A1是癌症患者预后和肿瘤糖酵解的关键基因。

In vitro experiments and tumor formation in nude mice suggested that targeting ALDH1A1 could inhibit tumor growth. Through further analysis of xenograft tumor models in immune-normal mice and flow cytometry, we found that deficiency in ALDH1A1 could promote immune system suppression of tumors in vivo.

体外实验和裸鼠肿瘤形成表明，靶向ALDH1A1可以抑制肿瘤生长。通过进一步分析免疫正常小鼠的异种移植肿瘤模型和流式细胞术，我们发现ALDH1A1的缺乏可以促进体内肿瘤的免疫系统抑制。

Specifically, RNA-seq analysis, combined with qPCR and western blot, identified the transcription factor ZBTB7B as downstream of ALDH1A1. The binding sites of the transcription factor ZBTB7B on the LDHA promoter region, which is responsible for regulating the rate-limiting enzyme gene LDHA in glycolysis, were determined using luciferase reporter gene detection and Chip-qPCR, respectively.

具体而言，RNA-seq分析与qPCR和蛋白质印迹相结合，将转录因子ZBTB7B鉴定为ALDH1A1的下游。分别使用荧光素酶报告基因检测和Chip-qPCR确定了负责调节糖酵解中限速酶基因LDHA的LDHA启动子区域上转录因子ZBTB7B的结合位点。

In addition, the increased SUMOylation of ZBTB7B stabilized its transcriptional activity. Further in vivo and in vitro experiments confirmed that the combination of targeting ALDH1A1 and ZBTB7B with immune checkpoint inhibitors could synergistically inhibit tumors in vivo. Finally, after conducting additional verification of patient tissue and clinical data, we have confirmed the potential translational value of targeting ALDH1A1 and ZBTB7B for tumor immunotherapy.

另外，ZBTB7B的SUMO化增加稳定了其转录活性。进一步的体内和体外实验证实，靶向ALDH1A1和ZBTB7B与免疫检查点抑制剂的组合可以协同抑制体内肿瘤。最后，在对患者组织和临床数据进行额外验证后，我们证实了靶向ALDH1A1和ZBTB7B用于肿瘤免疫治疗的潜在翻译价值。

These results emphasize the potential translational significance of targeting ALDH1A1 and ZBTB7B in the realm of tumor immunotherapy. The convergence of ALDH1A1 inhibition and immune checkpoint .

这些结果强调了在肿瘤免疫治疗领域靶向ALDH1A1和ZBTB7B的潜在翻译意义。ALDH1A1抑制和免疫检查点的融合。

IntroductionThe advent of contemporary immunotherapy represents a beacon of hope for patients grappling with various malignancies, particularly non-small cell lung cancer (NSCLC), which is characterized by a paucity of treatment options. This breakthrough marks a significant milestone in the landscape of cancer therapeutics [1].

引言当代免疫疗法的出现为患有各种恶性肿瘤的患者提供了希望的灯塔，特别是非小细胞肺癌（NSCLC），其特征是缺乏治疗选择。这一突破标志着癌症治疗领域的一个重要里程碑。

Immune checkpoint inhibitors (ICIs), typified by PD-1/PD-L1 inhibitors, have garnered considerable attention owing to their notable efficacy in treating a spectrum of solid tumors [2, 3]. However, the response rates to PD-L1/PD-1 blockade fall short of 40%, and certain patients manifest primary or secondary resistance to immunotherapy [4, 5].

以PD-1/PD-L1抑制剂为代表的免疫检查点抑制剂（ICI）由于其在治疗一系列实体瘤方面的显着功效而引起了相当大的关注[2，3]。然而，对PD-L1/PD-1阻断的反应率低于40%，某些患者表现出对免疫治疗的原发性或继发性耐药[4，5]。

The precise mechanisms underpinning tumor immune evasion remain elusive [6]. Therefore, comprehending the molecular intricacies governing the regulation of tumor immune escape assumes paramount importance, as it holds profound implications for refining the efficacy of anti-PD-L1/PD-1 therapy and shaping prognostic outcomes.Accumulating empirical evidence accentuates the pivotal role of tumor cell glycolysis not only in sustaining tumorigenesis and cellular survival but also in orchestrating the intricate interplay between tumor cells and immune cells through the release of lactate [7].

支持肿瘤免疫逃避的确切机制仍然难以捉摸（6）。因此，了解控制肿瘤免疫逃逸调节的分子复杂性至关重要，因为它对提高抗PD-L1/PD-1疗法的疗效和塑造预后结果具有深远的意义。积累的经验证据强调了肿瘤细胞糖酵解的关键作用，不仅在维持肿瘤发生和细胞存活方面，而且在通过释放乳酸来协调肿瘤细胞和免疫细胞之间错综复杂的相互作用方面。

Elevated concentrations of lactic acid can be internalized and metabolized as a crucial fuel substrate, thereby fostering tumor angiogenesis and facilitating tumor invasion and metastasis [8]. Moreover, heightened levels of lactic acid in the tumor microenvironment exert an immunosuppressive effect, activating the immune checkpoint PD-1 and instigating resistance against PD-L1/PD-1 therapy [9].

升高浓度的乳酸可以作为关键的燃料底物被内化和代谢，从而促进肿瘤血管生成并促进肿瘤侵袭和转移。此外，肿瘤微环境中乳酸水平的升高发挥免疫抑制作用，激活免疫检查点PD-1并引发对PD-L1/PD-1治疗的抵抗（9）。

Recent investigations underscore the ability of the key rate-limiting enzyme HK2 in glycolysis to activate the NF-κB pathway, thereby.

最近的研究强调了糖酵解中关键的限速酶HK2激活NF-κB途径的能力。

Data availability

数据可用性

All data needed to evaluate the conclusions are present in the paper. The RNA-seq data were deposited to the GEO database with the accession number GSE225822 and GSE269935. Other data and materials are available upon reasonable request.

本文提供了评估结论所需的所有数据。RNA-seq数据以登录号GSE225822和GSE269935保存到GEO数据库中。可根据合理要求提供其他数据和材料。

ReferencesZhang Y, Zhang Z. The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications. Cell Mol Immunol. 2020;17:807–21.Article

参考文献Zhang Y，Zhang Z.癌症免疫治疗的历史和进展：了解肿瘤浸润性免疫细胞的特征及其治疗意义。。2020年；17： 807-21.文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Doroshow DB, Bhalla S, Beasley MB, Sholl LM, Kerr KM, Gnjatic S, et al. PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nat Rev Clin Oncol. 2021;18:345–62.Article

。Nat Rev Clin Oncol。2021年；18： 345-62.文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Bagchi S, Yuan R, Engleman EG. Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance. Annu Rev Pathol. 2021;16:223–49.Article

Bagchi S，Yuan R，Engleman EG.用于治疗癌症的免疫检查点抑制剂：临床影响以及反应和耐药机制。Annu Rev Pathol公司。2021年；16： 223-49.条

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Yarchoan M, Hopkins A, Jaffee EM. Tumor Mutational Burden and Response Rate to PD-1 Inhibition. N. Engl J Med. 2017;377:2500–1.Article

Yarchoan M，Hopkins A，Jaffee EM.肿瘤突变负荷和对PD-1抑制的反应率。N、 英国医学杂志2017；377:2500–1.文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Pitt JM, Vétizou M, Daillère R, Roberti MP, Yamazaki T, Routy B, et al. Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors. Immunity. 2016;44:1255–69.Article

Pitt JM，Vétizou M，Daillère R，Roberti MP，Yamazaki T，Routy B等。癌症免疫检查点阻断的耐药机制：肿瘤内在和外在因素。豁免。2016年；44:1255–69.文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Gotwals P, Cameron S, Cipolletta D, Cremasco V, Crystal A, Hewes B, et al. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat Rev Cancer. 2017;17:286–301.Article

Gotwals P，Cameron S，Cipolletta D，Cremasco V，Crystal A，Hewes B等。将靶向和常规癌症治疗与免疫治疗相结合的前景。Nat Rev癌症。2017年；17： 286-301.文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Xia L, Oyang L, Lin J, Tan S, Han Y, Wu N, et al. The cancer metabolic reprogramming and immune response. Mol Cancer. 2021;20:28.Article

夏丽，欧阳丽，林杰，谭珊，韩艳，吴恩，等。癌症代谢重编程与免疫反应。摩尔癌症。2021年；20： 28、条款

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Rabinowitz JD, Enerbäck S. Lactate: the ugly duckling of energy metabolism. Nat Metab. 2020;2:566–71.Article

Rabinowitz JD，Enerbäck S.Lactate：能量代谢的丑小鸭。。2020年；2： 566-71.文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin Y-T, Togashi Y, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell. 2022;40:201–18.e9.Article

Kumagai S，Koyama S，Itahashi K，Tanegashima T，Lin Y-T，Togashi Y等。乳酸促进高度糖酵解肿瘤微环境中调节性T细胞中PD-1的表达。癌细胞。2022年；40:201–18.e9.文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Guo D, Tong Y, Jiang X, Meng Y, Jiang H, Du L, et al. Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα. Cell Metab. 2022;34:1312–24.e6.Article

郭D，Tong Y，Jiang X，Meng Y，Jiang H，Du L等。有氧糖酵解通过己糖激酶2介导的IκBα磷酸化促进肿瘤免疫逃避。细胞代谢。2022年；34:1312–24.e6.文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Jackson B, Brocker C, Thompson DC, Black W, Vasiliou K, Nebert DW, et al. Update on the aldehyde dehydrogenase gene (ALDH) superfamily. Hum Genomics. 2011;5:283.Article

Jackson B，Brocker C，Thompson DC，Black W，Vasiliou K，Nebert DW等。醛脱氢酶基因（ALDH）超家族的最新进展。Hum基因组学。2011年；5： 283条

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Arfaoui A, Rioualen C, Azzoni V, Pinna G, Finetti P, Wicinski J, et al. A genome-wide RNAi screen reveals essential therapeutic targets of breast cancer stem cells. EMBO Mol Med. 2019;11:e9930.Article

Arfaoui A，Rioualen C，Azzoni V，Pinna G，Finetti P，Wicinski J等。全基因组RNAi筛选揭示了乳腺癌干细胞的重要治疗靶点。EMBO Mol Med。2019；11： e9930。文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Wang Q, Jiang J, Ying G, Xie X-Q, Zhang X, Xu W, et al. Tamoxifen enhances stemness and promotes metastasis of ERα36+ breast cancer by upregulating ALDH1A1 in cancer cells. Cell Res. 2018;28:336–58.Article

Wang Q，Jiang J，Ying G，Xie X-Q，Zhang X，Xu W，et al。他莫昔芬通过上调癌细胞中的ALDH1A1来增强ERα36+乳腺癌的干性并促进其转移。Cell Res.2018；28:336–58.文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

van den Hoogen C, van der Horst G, Cheung H, Buijs JT, Lippitt JM, Guzmán-Ramírez N, et al. High Aldehyde Dehydrogenase Activity Identifies Tumor-Initiating and Metastasis-Initiating Cells in Human Prostate Cancer. Cancer Res. 2010;70:5163–73.Article

van den Hoogen C，van der Horst G，Cheung H，Buijs JT，Lippitt JM，Guzmán-Ramírez n等。高醛脱氢酶活性可鉴定人前列腺癌中的肿瘤起始细胞和转移起始细胞。癌症研究2010；70:5163–73.文章

PubMed

PubMed

Google Scholar

谷歌学者

Vassalli G. Aldehyde Dehydrogenases: Not Just Markers, but Functional Regulators of Stem Cells. Stem Cells Int. 2019;2019:e3904645.Article

Vassalli G.醛脱氢酶：不仅是标记物，而且是干细胞的功能调节剂。干细胞国际2019；2019年：e3904645.Article

Google Scholar

谷歌学者

Liu C, Qiang J, Deng Q, Xia J, Deng L, Zhou L, et al. ALDH1A1 Activity in Tumor-Initiating Cells Remodels Myeloid-Derived Suppressor Cells to Promote Breast Cancer Progression. Cancer Res. 2021;81:5919–34.Article

Liu C，Qiang J，Deng Q，Xia J，Deng L，Zhou L等。肿瘤起始细胞中的ALDH1A1活性重塑骨髓来源的抑制细胞以促进乳腺癌进展。癌症研究2021；81:5919–34.文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Lee S-U, Maeda T. POK/ZBTB proteins: an emerging family of proteins that regulate lymphoid development and function. Immunol Rev. 2012;247:107–19.Article

Lee S-U，Maeda T.POK/ZBTB蛋白：一种新兴的调节淋巴发育和功能的蛋白家族。Immunol Rev。2012；247:107–19.文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Constantinou C, Spella M, Chondrou V, Patrinos GP, Papachatzopoulou A, Sgourou A. The multi-faceted functioning portrait of LRF/ZBTB7A. Hum Genomics. 2019;13:66.Article

Constantinou C，Spella M，Chondou V，Patrinos GP，Papacatzopoulou A，Sgourou A.LRF/ZBTB7A的多方面功能肖像。Hum基因组学。2019年；13： 66、条款

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Liao J, Liu J, Wang J, Wang M. Lnc-CPLC promotes the progression of colorectal cancer via regulating ZBTB34 by competitively binding miR-4319. J Cell Physiol. 2022;237:1573–85.Article

Liao J，Liu J，Wang J，Wang M.Lnc-CPLC通过竞争性结合miR-4319调节ZBTB34来促进结直肠癌的进展。J细胞生理学。2022年；237:1573–85.文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Wang M, Liao J, Wang J, Qi M, Wang K, Wu W. TAF1A and ZBTB41 serve as novel key genes in cervical cancer identified by integrated approaches. Cancer Gene Ther. 2021;28:1298–311.Article

Wang M，Liao J，Wang J，Qi M，Wang K，Wu W.TAF1A和ZBTB41是通过综合方法鉴定的宫颈癌新关键基因。癌症基因治疗。2021年；28:1298–311.文章

PubMed

PubMed

Google Scholar

谷歌学者

Wang M, Zou J, Wang J, Liu M, Liu K, Wang N, et al. Aberrant HSF1 signaling activation underlies metformin amelioration of myocardial infarction in mice. Mol Ther Nucleic Acids. 2022;29:312–28.Article

Wang M，Zou J，Wang J，Liu M，Liu K，Wang N等。异常的HSF1信号激活是二甲双胍改善小鼠心肌梗塞的基础。分子核酸。2022年；29:312–28.文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Liao J, Chen H, Qi M, Wang J, Wang M. MLLT11-TRIL complex promotes the progression of endometrial cancer through PI3K/AKT/mTOR signaling pathway. Cancer Biol Ther. 2022;23:211–24.Article

Liao J，Chen H，Qi M，Wang J，Wang M.MLLT11-TRIL复合物通过PI3K/AKT/mTOR信号通路促进子宫内膜癌的进展。癌症生物学。2022年；23:211–24.文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

García-Cañaveras JC, Chen L, Rabinowitz JD. The Tumor Metabolic Microenvironment: Lessons from Lactate. Cancer Res. 2019;79:3155–62.Article

García-Cañaveras JC，Chen L，Rabinowitz JD。肿瘤代谢微环境：乳酸的教训。癌症研究2019；79:3155–62.文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Paul S, Ghosh S, Kumar S. Tumor glycolysis, an essential sweet tooth of tumor cells. Semin Cancer Biol. 2022;86:1216–30.Article

Paul S，Ghosh S，Kumar S.肿瘤糖酵解，肿瘤细胞必不可少的甜食。Semin癌症生物学。2022年；86:1216–30.文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Cui B, Luo Y, Tian P, Peng F, Lu J, Yang Y, et al. Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells. J Clin Invest. 2019;129:1030–46.Article

崔B，罗Y，田P，彭F，陆J，杨Y，等。应激诱导的肾上腺素增强乳酸脱氢酶A并促进乳腺癌干细胞样细胞。J临床投资。2019年；129:1030–46.文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Feron O. Pyruvate into lactate and back: from the Warburg effect to symbiotic energy fuel exchange in cancer cells. Radiother Oncol. 2009;92:329–33.Article

Feron O.丙酮酸转化为乳酸并返回：从Warburg效应到癌细胞中的共生能量燃料交换。Radiother Oncol。2009年；

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Pan T, Sun S, Chen Y, Tian R, Chen E, Tan R, et al. Immune effects of PI3K/Akt/HIF-1α-regulated glycolysis in polymorphonuclear neutrophils during sepsis. Crit Care. 2022;26:29.Article

Pan T，Sun S，Chen Y，Tian R，Chen E，Tan R，等。脓毒症期间多形核中性粒细胞中PI3K/Akt/HIF-1α调节的糖酵解的免疫作用。暴击护理。2022年；26:29.文章

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Sharma D, Singh M, Rani R. Role of LDH in tumor glycolysis: Regulation of LDHA by small molecules for cancer therapeutics. Semin Cancer Biol. 2022;87:184–95.Article

Sharma D，Singh M，Rani R.LDH在肿瘤糖酵解中的作用：小分子对LDHA的调节用于癌症治疗。Semin癌症生物学。2022年；87:184–95.文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Hua H, Kong Q, Zhang H, Wang J, Luo T, Jiang Y. Targeting mTOR for cancer therapy. J Hematol Oncol. 2019;12:71.Article

Hua H，Kong Q，Zhang H，Wang J，Luo T，Jiang Y.针对mTOR进行癌症治疗。J Hematol Oncol。2019年；12： 71、条款

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Zhang Z, Wang Y, Liang Z, Meng Z, Zhang X, Ma G, et al. Modification of lysine-260 2-hydroxyisobutyrylation destabilizes ALDH1A1 expression to regulate bladder cancer progression. iScience. 2023;26:108142.Article

Zhang Z，Wang Y，Liang Z，Meng Z，Zhang X，Ma G等。赖氨酸-260 2-羟基异丁酰化的修饰使ALDH1A1表达不稳定，从而调节膀胱癌的进展。iScience。2023年；26:108142.文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Triplett TA, Garrison KC, Marshall N, Donkor M, Blazeck J, Lamb C, et al. Reversal of indoleamine 2,3-dioxygenase–mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme. Nat Biotechnol. 2018;36:758–64.Article

Triplett TA，Garrison KC，Marshall N，Donkor M，Blazeck J，Lamb C等。用治疗性酶通过全身犬尿氨酸耗竭逆转吲哚胺2,3-双加氧酶介导的癌症免疫抑制。纳特生物技术。2018年；36:758–64.文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Sen T, Rodriguez BL, Chen L, Corte CMD, Morikawa N, Fujimoto J, et al. Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer. Cancer Discov. 2019;9:646–61.Article

Sen T，Rodriguez BL，Chen L，Corte CMD，Morikawa N，Fujimoto J等。靶向DNA损伤反应通过STING介导的小细胞肺癌T细胞活化促进抗肿瘤免疫。癌症发现。2019年；9： 646-61.文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Pajak B, Siwiak E, Sołtyka M, Priebe A, Zieliński R, Fokt I, et al. 2-Deoxy-d-Glucose and Its Analogs: From Diagnostic to Therapeutic Agents. Int J Mol Sci. 2019;21:234.Article

Pajak B，Siwiak E，Sołtyka M，Priebe A，Zieliński R，Fokt I等。2-脱氧-d-葡萄糖及其类似物：从诊断剂到治疗剂。国际分子科学杂志。2019年；

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Chefetz I, Grimley E, Yang K, Hong L, Vinogradova EV, Suciu R, et al. A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells. Cell Rep. 2019;26:3061–75.e6.Article

Chefetz I，Grimley E，Yang K，Hong L，Vinogradova EV，Suciu R等。泛ALDH1A抑制剂诱导卵巢癌干细胞样细胞坏死。细胞代表2019；26:3061–75.e6.文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Ivashkiv LB. The hypoxia-lactate axis tempers inflammation. Nat Rev Immunol. 2020;20:85–86.Article

Ivashkiv LB。缺氧-乳酸轴调节炎症。Nat Rev免疫。2020年；20： 85-86.文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Ye L, Jiang Y, Zhang M. Crosstalk between glucose metabolism, lactate production and immune response modulation. Cytokine Growth Factor Rev. 2022;68:81–92.Article

Ye L，Jiang Y，Zhang M.葡萄糖代谢，乳酸产生和免疫应答调节之间的串扰。细胞因子生长因子修订版2022；68:81–92.文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Wang Z-H, Peng W-B, Zhang P, Yang X-P, Zhou Q. Lactate in the tumour microenvironment: From immune modulation to therapy. EBioMedicine. 2021;73:103627.Article

Wang Z-H，Peng W-B，Zhang P，Yang X-P，Zhou Q.肿瘤微环境中的乳酸：从免疫调节到治疗。EBioMedicine。2021年；73:103627.文章

CAS

中科院

PubMed

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Venugopal A, Koi M, Choi C, Kim H-R, Speliotes EK, Carethers JM. ALDH1A1 Expression Is Enriched in Early-Onset Colorectal Cancers. Gastroenterology. 2022;163:1679–81.e1.Article

Venugopal A，Koi M，Choi C，Kim H-R，Speliotes EK，Carethers JM。ALDH1A1表达在早发性结直肠癌中富集。胃肠病学。2022年；

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Matic I, Schimmel J, Hendriks IA, van Santen MA, van de Rijke F, van Dam H, et al. Site-specific identification of SUMO-2 targets in cells reveals an inverted SUMOylation motif and a hydrophobic cluster SUMOylation motif. Mol Cell. 2010;39:641–52.Article

Matic I，Schimmel J，Hendriks IA，van Santen MA，van de Rijke F，van Dam H等。细胞中SUMO-2靶标的位点特异性鉴定揭示了倒置的SUMO化基序和疏水簇SUMO化基序。摩尔细胞。2010年；39:641–52.文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Guo H, Xu J, Zheng Q, He J, Zhou W, Wang K, et al. NRF2 SUMOylation promotes de novo serine synthesis and maintains HCC tumorigenesis. Cancer Lett. 2019;466:39–48.Article

郭H，徐J，郑Q，何J，周W，王K等。NRF2 SUMOylation促进从头丝氨酸合成并维持HCC肿瘤发生。癌症Lett。2019年；466:39–48.文章

CAS

中科院

PubMed

PubMed

Google Scholar

谷歌学者

Download referencesAcknowledgementsWe acknowledge the assistance of the Obstetrics and Gynecology team, Pathology team, and Oncology team of Zhuzhou Hospital affiliated to Xiangya School of Medicine in this study. We would like to thank BioRender (https://biorender.com/) for help with the construction of some of the schematics.FundingThis study was supported by the Natural Science Foundation of Hunan Province, China (2022JJ40818); Fuqing Talent Plan Project, Xiangya Hospital, Central South University (2209090555261); Xiangya Hospital, Central South University (XK60000692130); the Affiliated Zhuzhou Hospital Xiangya Medical College Grant (No.202008001).Author informationAuthors and AffiliationsDepartment of Geratic Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaMingyuan Wang & Xi LiNational Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaMingyuan Wang & Xi LiDepartment of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaMingyuan Wang & Xi LiDepartment of Pathology, the Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, Zhuzhou, Hunan, ChinaTaoli WangDepartment of Gynaecology, the Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, Zhuzhou, Hunan, ChinaJinjin Wang & Huan ChenDepartment of Oncology, the Affiliated Zhuzhou Hospital Xiangya Medical College, Central South University, Zhuzhou, Hunan, ChinaYuexin YangHunan Provincial Key Laboratory of Regional Hereditary Birth Defects Prevention and Control, Changsha Hospital for Maternal & Child Health Care Affiliated to Hunan Normal University, Changsha, ChinaJingnan LiaoAuthorsMingyuan WangView author publicationsYou can also s.

下载参考文献致谢我们感谢湘雅医学院附属株洲医院妇产科团队，病理团队和肿瘤团队在本研究中的协助。我们要感谢BioRender(https://biorender.com/)以帮助构建一些示意图。资助该研究得到了中国湖南省自然科学基金（2022JJ40818）的支持；中南大学湘雅医院福清人才计划项目（2209090555261）；；附属株洲医院湘雅医学院拨款（No.202008001）。作者信息作者和附属机构中南大学湘雅医院老年外科，湖南长沙，中国明远王和西国家老年疾病临床研究中心，中南大学湘雅医院，湖南长沙，中国明远王和西李中南大学湘雅医院普外科，湖南长沙，中国明远王和西李中南大学湘雅医学院附属株洲医院病理科，湖南株洲，中国桃李王中南大学湘雅医学院附属株洲医院妇科，湖南株洲中南大学附属株洲医院湘雅医学院，湖南株洲，湖南省区域遗传性出生缺陷预防与控制重点实验室，湖南师范大学附属长沙妇幼保健院，长沙，中国廖京南作者王明远作者出版物。

PubMed Google ScholarTaoli WangView author publicationsYou can also search for this author in

PubMed Google ScholarTaoli WangView作者出版物您也可以在

PubMed Google ScholarJinjin WangView author publicationsYou can also search for this author in

PubMed谷歌学者Jinjin WangView作者出版物您也可以在

PubMed Google ScholarYuexin YangView author publicationsYou can also search for this author in

PubMed Google ScholaryYexin YangView作者出版物您也可以在

PubMed Google ScholarXi LiView author publicationsYou can also search for this author in

PubMed Google ScholarXi LiView作者出版物您也可以在

PubMed Google ScholarHuan ChenView author publicationsYou can also search for this author in

PubMed Google ScholarHuan ChenView作者出版物您也可以在

PubMed Google ScholarJingnan LiaoView author publicationsYou can also search for this author in

PubMed Google ScholarJingnan LiaoView作者出版物您也可以在

PubMed Google ScholarContributionsMingyuan Wang conceived this study. Xi Li, Tiaoli Wang, Jinjin Wang, and Yuexin Yang performed the experiments and analyzed data. Jingnan Liao and Huan Chen directed and coordinated study, designed the research and oversaw the project. Jingnan Liao prepared the manuscript.

PubMed谷歌学术贡献王明远构思了这项研究。西丽，王条丽，王金金和杨跃欣进行了实验并分析了数据。廖京南和陈欢指导和协调研究，设计研究并监督项目。廖京南准备了手稿。

All authors read and approved the final manuscript.Corresponding authorsCorrespondence to.

所有作者都阅读并批准了最终稿件。通讯作者通讯。

Xi Li, Huan Chen or Jingnan Liao.Ethics declarations

西丽、陈欢或廖京南。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Ethics approval and consent to participate

道德批准和同意参与

The study was approved by the Ethics Review Committee of the Affiliated Zhuzhou Hospital of Xiangya School of Medicine, Central South University, and all included patients provided written informed consent. All methods were carried out in accordance with relevant guidelines and regulations. All animal experiments were carried out in accordance with the Laboratory Animal Welfare and Ethical Committee of Central South University..

该研究得到中南大学湘雅医学院附属株洲医院伦理审查委员会的批准，所有患者均提供了书面知情同意书。所有方法均按照相关指南和规定进行。所有动物实验均按照中南大学实验动物福利与伦理委员会的要求进行。。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Edited by Jean-Ehrland RicciSupplementary informationSupplementary materialUncropped WB imagesRights and permissions

Additional informationPublisher的注释Springer Nature在已发布的地图和机构隶属关系中的管辖权主张方面保持中立。由Jean Ehrland Riccis编辑补充信息补充材料不受限制的WB图像权限

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.

开放获取本文是根据知识共享署名4.0国际许可证授权的，该许可证允许以任何媒体或格式使用，共享，改编，分发和复制，只要您对原始作者和来源给予适当的信任，提供知识共享许可证的链接，并指出是否进行了更改。

The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

本文中的图像或其他第三方材料包含在文章的知识共享许可中，除非在材料的信用额度中另有说明。如果材料未包含在文章的知识共享许可中，并且您的预期用途不受法律法规的许可或超出许可用途，则您需要直接获得版权所有者的许可。

To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/..

要查看此许可证的副本，请访问http://creativecommons.org/licenses/by/4.0/..

Reprints and permissionsAbout this articleCite this articleWang, M., Wang, T., Wang, J. et al. ALDH1A1 promotes immune escape of tumor cells through ZBTB7B-glycolysis pathway.

转载和许可本文引用本文Wang，M.，Wang，T.，Wang，J。等人。ALDH1A1通过ZBTB7B糖酵解途径促进肿瘤细胞的免疫逃逸。

Cell Death Dis 15, 568 (2024). https://doi.org/10.1038/s41419-024-06943-9Download citationReceived: 09 March 2024Revised: 18 July 2024Accepted: 23 July 2024Published: 07 August 2024DOI: https://doi.org/10.1038/s41419-024-06943-9Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

细胞死亡Dis 15568（2024）。https://doi.org/10.1038/s41419-024-06943-9Download引文收到日期：2024年3月9日修订日期：2024年7月18日接受日期：2024年7月23日发布日期：2024年8月7日OI：https://doi.org/10.1038/s41419-024-06943-9Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

Provided by the Springer Nature SharedIt content-sharing initiative

由Springer Nature SharedIt内容共享计划提供