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摘要: 脑胶质瘤为发病率最高的中枢神经系统原发性恶性肿瘤，恶性程度高，患者预后差。目前，脑胶质瘤领域的研究主要聚焦于肿瘤发生机制探究、新治疗手段及药物研发方面，在胶质瘤分子病理分型优化、影像检查诊断技术提升及综合治疗指南制订方面亦开展了深入研究。本文将对2021年度我国脑胶质瘤领域的研究成果及重要进展进行阐述，并对未来可能的研究方向进行展望，以期为临床研究提供借鉴和参考。Abstract: Glioma, the most prevalent primary malignant tumor of the central nervous system, has a high degree of malignancy and poor prognosis for patients. At present, the researches of glioma mainly focus on the investigation of the mechanism of tumor occurrence and the discovery of new therapeutic methods and agents. In-depth researches have also been conducted on the optimization of molecular pathological typing of glioma, improvement of diagnostic imaging techniques and formulation of comprehensive treatment guidelines. In this review, we summarize the achievements and important progress made by Chinese medical scientists in the field of glioma in 2021, and propose possible future research directions with the aim of providing reference for clinical research.
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Keywords:
- glioma /
- magnetic resonance imaging /
- temozolomide /
- targeted therapy /
- immune microenvironment
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丝氨酸蛋白酶是一类以丝氨酸为活性中心的蛋白水解酶，在胚胎发育、组织重构、细胞分化、血管形成等多种生理过程中均发挥重要作用。丝氨酸蛋白酶抑制剂(serine proteinase inhibitors，serpins)超家族是一类大小相似、结构高度保守的蛋白质分子，几乎存在于所有生命体中，目前已发现超过1000个家族成员，serpins可作为自杀性底物与丝氨酸蛋白酶结合，通过形成共价抑制复合物而调节丝氨酸蛋白酶的活性，参与调控体内一系列蛋白水解级联反应，如补体激活、凝血、细胞凋亡等。根据系统进化研究，serpins被分为16个亚家族[1]，其中人类基因组可编码9个亚家族(A~I族)serpins[2]。B族serpins被称为卵清蛋白样丝氨酸蛋白酶抑制剂，与其他大多数serpins为细胞外蛋白不同，B族serpins缺乏经典的N末端信号肽，主要存在于细胞质与细胞核中，保护细胞免受外源性和内源性蛋白酶介导的损伤[3]。
SerpinB9是B族serpins成员之一，是颗粒酶B(granzyme B，GrB)的生理性抑制剂，存在于多种免疫细胞中，参与人体内病毒感染、免疫应答、炎症反应、肿瘤发生等多种过程。已有研究发现SerpinB9与冠状动脉粥样硬化、糖尿病等疾病相关[4]。近年来，SerpinB9在肿瘤发生发展中的作用成为研究热点，并有望成为肿瘤治疗的潜在靶点之一。皮肤恶性肿瘤种类繁多，晚期进展迅速、预后差，尚无有效的治疗手段，研究SerpinB9在皮肤肿瘤发生中的作用并探索其作为治疗靶点的可能性具有重要临床意义。本文将对SerpinB9与肿瘤的关系及其在皮肤肿瘤领域的研究进展进行综述。
1. SerpinB9功能
通过死亡受体途径和细胞毒性颗粒诱导细胞凋亡是自然杀伤(natural killer，NK)细胞和细胞毒性T淋巴细胞(cytotoxic T lymphocyte，CTL)杀灭靶细胞的主要方式，细胞毒性颗粒内含有可溶解细胞膜的穿孔素及多种颗粒酶，其中GrB是诱导靶细胞凋亡的主要效应因子。GrB是一种外源性丝氨酸蛋白酶，可与靶细胞表面的磷酸甘露糖受体结合并进入细胞，激活含半胱氨酸的天冬氨酸蛋白水解酶(cysteinyl aspartate specific proteinase，caspase)-3、caspase-7等，导致DNA裂解并启动细胞凋亡[5]。
Sun等[6]研究发现, SerpinB9是GrB的生理性抑制剂，通过与GrB结合形成共价复合物而抑制其功能，进而抑制穿孔素/颗粒酶途径介导的细胞凋亡，并发现SerpinB9主要存在于CTL及B细胞中，推测在免疫应答过程中，淋巴细胞通过产生SerpinB9灭活内源性或外源性GrB，从而抵抗GrB对自身的杀伤作用，其为淋巴细胞的自我保护机制之一。随后的多项研究均证实了这一观点[7-8]。Bird等[9]通过研究进一步证实, SerpinB9可特异性抑制GrB而不影响Fas介导的细胞凋亡，使CTL可通过Fas途径进行自我清除，从而维持免疫系统的稳态。近年来，一些研究表明SerpinB9同样可与活化的caspase-8、caspase-10相互作用，抑制下游caspase的激活，进而抑制肿瘤坏死因子(tumor necrosis factor，TNF)、TNF相关凋亡诱导配体(TNF related apoptosis-inducing ligand，TRAIL)、Fas等死亡受体途径介导的细胞凋亡[10-11]。
2. SerpinB9分布
SerpinB9分布广泛，除在CTL中发挥自我保护作用外，在树突状细胞、调节性T淋巴细胞、脾边缘区B淋巴细胞、肥大细胞等免疫细胞，以及血管内皮细胞、间皮细胞中同样可检测到SerpinB9的表达。通过抑制其在免疫应答过程中可能接触到的内源性或外源性GrB而避免了异常自身凋亡，从而发挥抗原交叉提呈、启动免疫反应、保持血管完整性等生理作用[12-16]。此外，免疫豁免部位的细胞，如胎盘组织的中间滋养细胞、睾丸支持细胞、卵巢颗粒细胞和晶状体细胞也可产生SerpinB9以保护自身免受免疫系统攻击，维持免疫系统稳态[12]。
3. SerpinB9与肿瘤发生发展及预后的关系
CTL的杀伤作用是机体实现抗肿瘤免疫的主要途径，而肿瘤细胞可通过多种途径逃脱免疫监视以促进肿瘤细胞增殖与转移，如下调主要组织相容性复合体(major histocompatibility complex，MHC)-Ⅰ类分子的表达、产生凋亡抑制蛋白c-FLIP进而抑制死亡受体途径介导的细胞凋亡等[5, 17]。近年来，SerpinB9在肿瘤发生发展中的作用成为研究的热点。Medema等[5]在人和小鼠的乳腺癌细胞、宫颈癌细胞、结肠癌细胞中均检测到SerpinB9表达，而在正常乳腺上皮细胞、宫颈上皮细胞、结肠上皮细胞中未发现SerpinB9表达，且SerpinB9高表达可显著抑制CTL通过穿孔素/颗粒酶途径介导的肿瘤细胞凋亡，表明SerpinB9的表达是肿瘤细胞抵抗CTL介导的细胞凋亡从而实现免疫逃逸的机制之一，而SerpinB9的表达水平可用于评估CTL介导的肿瘤免疫治疗可行性。
Rousalova等[18]研究证实非小细胞肺癌细胞和组织表达SerpinB9，且可抑制GrB的活性。Soriano等[19]研究发现，与正常支气管上皮细胞相比，肺癌细胞中SerpinB9表达升高，而肿瘤相关CD8+T细胞中GrB的表达水平下调; 且在非小细胞肺癌中，随着肿瘤进展SerpinB9的表达逐渐上升，表明SerpinB9表达升高与预后不良相关。Zhou等[20]在肝癌细胞中发现了类似结果，肝癌细胞中SerpinB9的表达水平显著高于正常肝组织，SerpinB9的表达水平与肿瘤分化程度、TNM分期、肿瘤体积呈正相关，且是肝细胞癌患者预后的独立预测因子，SerpinB9高表达组患者的生存时间显著短于SerpinB9低表达组。Vycital等[21]发现结直肠癌患者的肿瘤组织和正常结肠组织中均可检测到SerpinB9的表达，且正常结肠组织中SerpinB9表达升高的患者总生存期更长，推测该结果体现了抗肿瘤免疫反应与肿瘤细胞的相互作用对预后的影响，但其具体机制仍需进一步研究。Ray等[22]发现早期前列腺癌细胞中SerpinB9表达升高，并可抑制NK细胞释放的GrB介导的细胞凋亡，表明SerpinB9表达上调可能是促进早期前列腺癌进展的机制之一。
除实体肿瘤外，一些血液系统肿瘤细胞同样也表达SerpinB9。Fritsch等[23]发现淋巴细胞白血病、急性髓系白血病的肿瘤细胞表达SerpinB9，且SerpinB9表达水平与GrB活性呈负相关。随着SerpinB9表达水平升高，其对GrB的抑制程度增加，肿瘤细胞的凋亡水平降低，推测SerpinB9可通过抑制GrB减少肿瘤细胞凋亡，进而促进肿瘤免疫逃逸。Chen等[24]研究发现在对硼替佐米抵抗的复发难治性多发性骨髓瘤患者中，其骨髓单个核细胞的SerpinB9表达水平显著高于多发性骨髓瘤的新诊初治患者，功能富集分析提示SerpinB9参与调节细胞凋亡、程序性细胞死亡和免疫应答等过程，推测SerpinB9有望成为复发难治性多发性骨髓瘤的潜在治疗靶点和生物标志物。
4. SerpinB9与皮肤肿瘤
4.1 SerpinB9与恶性黑色素瘤
4.1.1 促进恶性黑色素瘤细胞免疫逃逸
在皮肤肿瘤领域关于SerpinB9的研究中，恶性黑色素瘤是报道最多、研究较为广泛的疾病。Medema等[5]发现在恶性黑色素瘤细胞中可检测到SerpinB9表达，SerpinB9通过灭活GrB抵抗CTL对肿瘤细胞的杀伤作用，而在正常黑色素细胞中SerpinB9表达阴性，表明恶性黑色素瘤细胞可能通过表达SerpinB9逃脱免疫系统的攻击与杀伤作用。
在恶性黑色素瘤治疗方面，免疫治疗是近年来的研究热点之一。多项研究表明，SerpinB9的表达水平与恶性黑色素瘤对免疫治疗的反应相关。在接受特异性主动免疫治疗的转移性恶性黑色素瘤患者中，肿瘤细胞表达SerpinB9的患者对免疫治疗反应较差，且预后不良，提示肿瘤细胞表达SerpinB9可能为一种重要的免疫逃逸机制，调控SerpinB9的表达水平可能是增强免疫治疗疗效的途径之一[25]。在使用免疫检查点抑制剂抗CTLA-4单克隆抗体易普利姆玛(ipilimumab)治疗恶性黑色素瘤的临床研究中发现，治疗有效组患者的SerpinB9表达水平较无应答组更低，SerpinB9表达水平升高与患者预后不良显著相关[26-27]。Jiang等[27]进一步研究发现，SerpinB9高表达与恶性黑色素瘤对免疫检查点抑制剂治疗抵抗相关，而恶性黑色素瘤细胞对免疫检查点抑制剂的治疗反应与CTL介导的肿瘤细胞凋亡密切相关。实验表明，敲除SERPINB9基因的B16F10细胞(小鼠皮肤黑色素瘤细胞)对CTL介导的细胞杀伤作用更敏感；而SERPINB9基因过表达的B16F10细胞对T细胞介导的细胞杀伤作用表现出抵抗。
4.1.2 通过影响肿瘤微环境促进恶性黑色素瘤发展
SerpinB9除在肿瘤细胞中表达增高以促进免疫逃逸、免疫治疗抵抗外，还可通过影响肿瘤微环境(tumor microenvironment，TME)，进而促进肿瘤发展。
TME包括肿瘤细胞周围的免疫细胞、成纤维细胞、血管、信号分子和细胞外基质等，TME与肿瘤细胞不断相互作用，进而影响肿瘤的生长、进展、转移、免疫逃逸等生物学行为[28]。TME中的髓源性抑制细胞(myeloid-derived suppressor cell，MDSC)、肿瘤相关巨噬细胞(tumor-associated macrophage，TAM)及调节性T(regulatory T，Treg)细胞等免疫细胞构成了免疫抑制性TME，促进肿瘤细胞的生长与侵袭。而TME中的间质细胞，如肿瘤相关成纤维细胞(tumor-associated fibroblast，CAF)可分泌多种细胞因子、趋化因子、基质蛋白等，阻碍效应T细胞对肿瘤细胞的杀伤作用，进而促进肿瘤发展[29-30]。
Luo等[31]对葡萄膜黑色素瘤TME中的免疫细胞和基质细胞的基因表达进行对比分析，发现了包括SERPINB9基因在内的21个与预后相关的基因。Jiang等[29]研究发现，恶性黑色素瘤TME中的MDSC、TAM、Treg细胞等抑制性免疫细胞同样表达SerpinB9，并通过抑制杀伤性淋巴细胞(CTL、NK细胞)分泌的或内源性GrB而发挥自我保护作用，进而形成有利于肿瘤生长、转移的TME，促进肿瘤发展。该团队还通过实验证实在SERPINB9基因缺陷的恶性黑色素瘤小鼠中，Treg、MDSC、TAM的比例及CAF的数目较对照组明显减少，提示抑制SerpinB9可逆转免疫抑制性TME，增强宿主的抗肿瘤免疫活性，并通过抑制肿瘤间质细胞的功能阻碍肿瘤的发展。
4.2 SerpinB9与皮肤鳞状细胞癌
器官移植后继发皮肤鳞状细胞癌是其严重并发症之一，Peters等[32]对肾移植患者的循环T细胞进行了全基因组甲基化分析，发现肾移植后继发皮肤鳞状细胞癌患者的T细胞中SERPINB9基因的甲基化水平显著高于非鳞状细胞癌，且外周T细胞中SerpinB9的表达水平低于对照组。推测T细胞中SERPINB9基因的表观遗传调控紊乱可能与皮肤鳞状细胞癌的发病相关，但其机制仍需进一步研究，通过表观修饰降低SERPINB9基因甲基化水平或许是预防移植后鳞状细胞癌的靶点之一。
4.3 SerpinB9与皮肤淋巴瘤
皮肤淋巴瘤是一组异质性疾病，原发性皮肤淋巴瘤的发生率在结外非霍奇金淋巴瘤中占第2位，同时原发结内的淋巴瘤也可出现皮肤受累。已有研究证实，在系统性间变性大细胞淋巴瘤，结外NK/T细胞淋巴瘤，鼻型、弥漫性大B细胞淋巴瘤和霍奇金淋巴瘤中均可检测到SerpinB9表达阳性的瘤细胞[33-34]。ten Berge等[34]研究发现，在系统性间变性大细胞淋巴瘤患者中，SerpinB9表达阳性的肿瘤细胞数目升高是预后不良的标志。Bossard等[35]对48例结外NK/T细胞淋巴瘤，鼻型患者的肿瘤细胞的SerpinB9表达水平与预后情况的分析表明，SerpinB9表达缺失是预后不良的标志，推测由于NK细胞固有表达GrB和SerpinB9，SerpinB9的“丢失”提示肿瘤细胞去分化，因此此类患者进展较快且预后差。
5. SerpinB9可能成为肿瘤治疗的潜在靶点
基于SerpinB9在肿瘤发生发展中的作用，通过抑制SerpinB9发挥抗肿瘤作用成为近年来研究的热点。SerpinB9可抑制CTL通过穿孔素/颗粒酶途径介导的肿瘤细胞凋亡，因此SerpinB9的表达水平是预测肿瘤细胞对CTL介导的杀伤作用的敏感性参数之一[25]。如前所述，复发性难治性多发性骨髓瘤患者的肿瘤细胞中SerpinB9表达水平较对照组显著增高，且SerpinB9在免疫应答、细胞凋亡等多种生理过程中发挥调控作用，提示SerpinB9有望成为复发难治性多发性骨髓瘤的潜在治疗靶点[24]。
Jiang等[29]筛选出了一种SerpinB9特异性抑制剂——小分子化合物3034(1，3-苯并恶唑-6-羧酸)，并通过实验证实了1，3-苯并恶唑-6-羧酸作用于恶性黑色素瘤细胞后可显著提高其凋亡率，降低黑色素瘤的生长速度，且在乳腺癌、肾癌、肺癌小鼠模型中均被证实具有类似的抗肿瘤效果。上述结论表明SerpinB9抑制剂具有潜在的抗肿瘤作用，可能成为多种恶性肿瘤治疗的新靶点。
6. 小结
综上所述，SerpinB9已被证实与非小细胞肺癌、肝癌、多发性骨髓瘤等多种恶性肿瘤相关，并通过促进免疫逃逸、影响TME等途径促进肿瘤的发生发展。在皮肤肿瘤方面，目前关于SerpinB9的研究主要集中于恶性黑色素瘤，而在其他皮肤恶性肿瘤中的表达及作用机制仍需进一步研究探索。目前研究数据显示，SerpinB9在肿瘤治疗方面具有较大潜力，为恶性黑色素瘤、鳞状细胞癌及皮肤淋巴瘤等难治性皮肤肿瘤的治疗提供了新的思路和方向。
作者贡献：陈雯琳、王雅宁、邢浩、梁庭毓、石易鑫、王海、杨蕙钰、刘千舒、李俊霖负责文献资料收集和论文初稿撰写；陈雯琳、郭晓鹏负责论文修订及整理；王裕、马文斌负责论文构思、写作指导及修订。利益冲突：所有作者均声明不存在利益冲突 -
[1] Sung H, Ferlay J, Siegel RL, 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: 209-249. DOI: 10.3322/caac.21660
[2] Chen F, Wendl MC, Wyczalkowski MA, et al. Moving pan-cancer studies from basic research toward the clinic[J]. Nat Cancer, 2021, 2: 879-890. DOI: 10.1038/s43018-021-00250-4
[3] Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase Ⅲ study: 5-year analysis of the EORTC-NCIC trial[J]. Lancet Oncol, 2009, 10: 459-466. DOI: 10.1016/S1470-2045(09)70025-7
[4] Stupp R, Taillibert S, Kanner A, et al. Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial[J]. JAMA, 2017, 318: 2306-2316. DOI: 10.1001/jama.2017.18718
[5] Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary[J]. Neuro Oncol, 2021, 23: 1231-1251. DOI: 10.1093/neuonc/noab106
[6] Wong QH, Li KK, Wang WW, et al. Molecular landscape of IDH-mutant primary astrocytoma Grade Ⅳ/glioblastomas[J]. Mod Pathol, 2021, 34: 1245-1260. DOI: 10.1038/s41379-021-00778-x
[7] Jin L, Shi F, Chun Q, et al. Artificial intelligence neuropathologist for glioma classification using deep learning on hematoxylin and eosin stained slide images and molecular markers[J]. Neuro Oncol, 2021, 23: 44-52. DOI: 10.1093/neuonc/noaa163
[8] Wen PY, Packer RJ. The 2021 WHO Classification of Tumors of the Central Nervous System: clinical implications[J]. Neuro Oncol, 2021, 23: 1215-1217. DOI: 10.1093/neuonc/noab120
[9] Mohile NA, Messersmith H, Gatson NT, et al. Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline[J]. J Clin Oncol, 2022, 40: 403-426.
[10] Jiang T, Nam DH, Ram Z, et al. Clinical practice guidelines for the management of adult diffuse gliomas[J]. Cancer Lett, 2021, 499: 60-72. DOI: 10.1016/j.canlet.2020.10.050
[11] Gao A, Zhang H, Yan X, et al. Whole-Tumor Histogram Analysis of Multiple Diffusion Metrics for Glioma Genotyping[J]. Radiology, 2022, 302: 652-661. DOI: 10.1148/radiol.210820
[12] Sun Q, Chen Y, Liang C, et al. Biologic Pathways Underlying Prognostic Radiomics Phenotypes from Paired MRI and RNA Sequencing in Glioblastoma[J]. Radiology, 2021, 301: 654-663. DOI: 10.1148/radiol.2021203281
[13] Xie R, Wu Z, Zeng F, et al. Retro-enantio isomer of angiopep-2 assists nanoprobes across the blood-brain barrier for targeted magnetic resonance/fluorescence imaging of glio-blastoma[J]. Signal Transduct Target Ther, 2021, 6: 309. DOI: 10.1038/s41392-021-00724-y
[14] Yang J, Zhao C, Lim J, et al. Structurally symmetric near-infrared fluorophore IRDye78-protein complex enables multimodal cancer imaging[J]. Theranostics, 2021, 11: 2534-2549. DOI: 10.7150/thno.54928
[15] Li Z, Kong Z, Chen J, et al. (18)F-Boramino acid PET/CT in healthy volunteers and glioma patients[J]. Eur J Nucl Med Mol Imaging, 2021, 48: 3113-3121. DOI: 10.1007/s00259-021-05212-7
[16] Zhang Y, Xi K, Fu X, et al. Versatile metal-phenolic network nanoparticles for multitargeted combination therapy and magnetic resonance tracing in glioblastoma[J]. Biomaterials, 2021, 278: 121163. DOI: 10.1016/j.biomaterials.2021.121163
[17] Huang N, Li F, Zhang M, et al. An Upstream Open Reading Frame in Phosphatase and Tensin Homolog Encodes a Circuit Breaker of Lactate Metabolism[J]. Cell Metab, 2021, 33: 128-144. e9. DOI: 10.1016/j.cmet.2020.12.008
[18] Wu X, Xiao S, Zhang M, et al. A novel protein encoded by circular SMO RNA is essential for Hedgehog signaling activation and glioblastoma tumorigenicity[J]. Genome Biol, 2021, 22: 33. DOI: 10.1186/s13059-020-02250-6
[19] Wang X, Zhou R, Xiong Y, et al. Sequential fate-switches in stem-like cells drive the tumorigenic trajectory from human neural stem cells to malignant glioma[J]. Cell Res, 2021, 31: 684-702. DOI: 10.1038/s41422-020-00451-z
[20] 中国医师协会脑胶质瘤专业委员会, 中国抗癌协会脑胶质瘤专业委员会, 中国脑胶质瘤协作组. 成人丘脑胶质瘤手术治疗中国专家共识[J]. 临床神经外科杂志, 2022, 19: 1-10. DOI: 10.3969/j.issn.1672-7770.2022.01.001 Society for NeuroOncology of China, Chinese Anti-Cancer Association Committee of the Glioma, Chinese Glioma Cooperative Group. Chinese experts consensus on surgical treatment for adult thalamus glioma[J]. Linchuang Shenjing Waike Zazhi, 2022, 19: 1-10. DOI: 10.3969/j.issn.1672-7770.2022.01.001
[21] Niu X, Yang Y, Zhou X, et al. A prognostic nomogram for patients with newly diagnosed adult thalamic glioma in a surgical cohort[J]. Neuro Oncol, 2021, 23: 337-338. DOI: 10.1093/neuonc/noaa268
[22] Hou Z, Zhang K, Liu X, et al. Molecular subtype impacts surgical resection in low-grade gliomas: A Chinese Glioma Genome Atlas database analysis[J]. Cancer Lett, 2021, 522: 14-21. DOI: 10.1016/j.canlet.2021.09.008
[23] Lu J, Zhao Z, Zhang J, et al. Functional maps of direct electrical stimulation-induced speech arrest and anomia: a multicentre retrospective study[J]. Brain, 2021, 144: 2541-2553. DOI: 10.1093/brain/awab125
[24] Sun R, Cuthbert H, Watts C. Fluorescence-Guided Surgery in the Surgical Treatment of Gliomas: Past, Present and Future[J]. Cancers (Basel), 2021, 13: 3508. DOI: 10.3390/cancers13143508
[25] Gao XY, Zang J, Zheng MH, et al. Temozolomide Treatment Induces HMGB1 to Promote the Formation of Glioma Stem Cells via the TLR2/NEAT1/Wnt Pathway in Glioblastoma[J]. Front Cell Dev Biol, 2021, 9: 620883. DOI: 10.3389/fcell.2021.620883
[26] Zheng Y, Liu L, Wang Y, et al. Glioblastoma stem cell (GSC)-derived PD-L1-containing exosomes activates AMPK/ULK1 pathway mediated autophagy to increase temozolomide-resistance in glioblastoma[J]. Cell Biosci, 2021, 11: 63. DOI: 10.1186/s13578-021-00575-8
[27] Wang Z, Wang Y, Yang T, et al. Machine learning revealed stemness features and a novel stemness-based classification with appealing implications in discriminating the prognosis, immunotherapy and temozolomide responses of 906 glioblastoma patients[J]. Brief Bioinform, 2021, 22: bbab032. DOI: 10.1093/bib/bbab032
[28] Li J, Kaneda MM, Ma J, et al. PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response[J]. Proc Natl Acad Sci U S A, 2021, 118: e2009290118. DOI: 10.1073/pnas.2009290118
[29] Li Z, Meng X, Wu P, et al. Glioblastoma Cell-Derived lncRNA-Containing Exosomes Induce Microglia to Produce Complement C5, Promoting Chemotherapy Resistance[J]. Cancer Immunol Res, 2021, 9: 1383-1399. DOI: 10.1158/2326-6066.CIR-21-0258
[30] Zhang XN, Yang KD, Chen C, et al. Pericytes augment glioblastoma cell resistance to temozolomide through CCL5-CCR5 paracrine signaling[J]. Cell Res, 2021, 31: 1072-1087. DOI: 10.1038/s41422-021-00528-3
[31] Oldrini B, Vaquero-Siguero N, Mu Q, et al. MGMT genomic rearrangements contribute to chemotherapy resis-tance in gliomas[J]. Nat Commun, 2020, 11: 3883. DOI: 10.1038/s41467-020-17717-0
[32] Shi J, Chen G, Dong X, et al. METTL3 Promotes the Resistance of Glioma to Temozolomide via Increasing MGMT and ANPG in a m6A Dependent Manner[J]. Front Oncol, 2021, 11: 702983. DOI: 10.3389/fonc.2021.702983
[33] Li F, Chen S, Yu J, et al. Interplay of m6 A and histone modifications contributes to temozolomide resistance in glioblastoma[J]. Clin Transl Med, 2021, 11: e553.
[34] Yuan Q, Yang W, Zhang S, et al. Inhibition of mitochondrial carrier homolog 2 (MTCH2) suppresses tumor invasion and enhances sensitivity to temozolomide in malignant glioma[J]. Mol Med, 2021, 27: 7.
[35] Yang W, Yuan Q, Zhang S, et al. Elevated GIGYF2 expression suppresses tumor migration and enhances sensitivity to temozolomide in malignant glioma[J]. Cancer Gene Ther, 2022, 29: 750-757. DOI: 10.1038/s41417-021-00353-1
[36] Wang K, Kievit FM, Chiarelli PA, et al. siRNA nanoparticle suppresses drug-resistant gene and prolongs survival in an orthotopic glioblastoma xenograft mouse model[J]. Adv Funct Mater, 2021, 31: 2007166. DOI: 10.1002/adfm.202007166
[37] Yang Q, Zhou Y, Chen J, et al. Gene Therapy for Drug-Resistant Glioblastoma via Lipid-Polymer Hybrid Nanopar-ticles Combined with Focused Ultrasound[J]. Int J Nanomedicine, 2021, 16: 185-199. DOI: 10.2147/IJN.S286221
[38] Liu Y, Bao Q, Chen Z, et al. Circumventing Drug Resistance Pathways with a Nanoparticle-Based Photodynamic Method[J]. Nano Lett, 2021, 21: 9115-9123. DOI: 10.1021/acs.nanolett.1c02803
[39] Hu H, Mu Q, Bao Z, et al. Mutational Landscape of Secondary Glioblastoma Guides MET-Targeted Trial in Brain Tumor[J]. Cell, 2018, 175: 1665-1678. e1618. DOI: 10.1016/j.cell.2018.09.038
[40] Wen PY, Stein A, van den Bent M, et al. Dabrafenib plus trametinib in patients with BRAF(V600E)-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial[J]. Lancet Oncol, 2022, 23: 53-64. DOI: 10.1016/S1470-2045(21)00578-7
[41] Yang Q, Guo C, Lin X, et al. Anlotinib Alone or in Combination With Temozolomide in the Treatment of Recurrent High-Grade Glioma: A Retrospective Analysis[J]. Front Pharmacol, 2021, 12: 804942. DOI: 10.3389/fphar.2021.804942
[42] Lombardi G, De Salvo GL, Brandes AA, et al. Regora-fenib compared with lomustine in patients with relapsed glioblastoma (REGOMA): a multicentre, open-label, randomised, controlled, phase 2 trial[J]. Lancet Oncol, 2019, 20: 110-119. DOI: 10.1016/S1470-2045(18)30675-2
[43] Lim M, Xia Y, Bettegowda C, et al. Current state of immunotherapy for glioblastoma[J]. Nat Rev Clin Oncol, 2018, 15: 422-442. DOI: 10.1038/s41571-018-0003-5
[44] Fares J, Ahmed AU, Ulasov IV, et al. Neural stem cell delivery of an oncolytic adenovirus in newly diagnosed malignant glioma: a first-in-human, phase 1, dose-escalation trial[J]. Lancet Oncol, 2021, 22: 1103-1114. DOI: 10.1016/S1470-2045(21)00245-X
[45] Vitanza NA, Johnson AJ, Wilson AL, et al. Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis[J]. Nat Med, 2021, 27: 1544-1552. DOI: 10.1038/s41591-021-01404-8
[46] Gao X, Xia X, Li F, et al. Circular RNA-encoded oncogenic E-cadherin variant promotes glioblastoma tumorigeni-city through activation of EGFR-STAT3 signalling[J]. Nat Cell Biol, 2021, 23: 278-291. DOI: 10.1038/s41556-021-00639-4
[47] Hasan MN, Luo L, Ding D, et al. Blocking NHE1 stimulates glioma tumor immunity by restoring OXPHOS function of myeloid cells[J]. Theranostics, 2021, 11: 1295-1309. DOI: 10.7150/thno.50150
[48] Chen Q, Jin J, Huang X, et al. EMP3 mediates glioblastoma-associated macrophage infiltration to drive T cell exclusion[J]. J Exp Clin Cancer Res, 2021, 40: 160. DOI: 10.1186/s13046-021-01954-2
[49] Wang QW, Sun LH, Zhang Y, et al. MET overexpression contributes to STAT4-PD-L1 signaling activation associated with tumor-associated, macrophages-mediated immunosuppression in primary glioblastomas[J]. J Immunother Cancer, 2021, 9: e002451. DOI: 10.1136/jitc-2021-002451
[50] Amoozgar Z, Kloepper J, Ren J, et al. Targeting Treg cells with GITR activation alleviates resistance to immunotherapy in murine glioblastomas[J]. Nat Commun, 2021, 12: 2582. DOI: 10.1038/s41467-021-22885-8
[51] Cao Y, Ding S, Zeng L, et al. Reeducating Tumor-Associated Macrophages Using CpG@Au Nanocomposites to Modulate Immunosuppressive Microenvironment for Improved Radio-Immunotherapy[J]. ACS Appl Mater Interfaces, 2021, 13: 53504-53518. DOI: 10.1021/acsami.1c07626
[52] Fan Y, Cui Y, Hao W, et al. Carrier-free highly drug-loaded biomimetic nanosuspensions encapsulated by cancer cell membrane based on homology and active targeting for the treatment of glioma[J]. Bioact Mater, 2021, 6: 4402-4414. DOI: 10.1016/j.bioactmat.2021.04.027
[53] Wang Y, Jiang Y, Wei D, et al. Nanoparticle-mediated convection-enhanced delivery of a DNA intercalator to gliomas circumvents temozolomide resistance[J]. Nat Biomed Eng, 2021, 5: 1048-1058. DOI: 10.1038/s41551-021-00728-7
[54] Miao YB, Chen KH, Chen CT, et al. A Noninvasive Gut-to-Brain Oral Drug Delivery System for Treating Brain Tumors[J]. Adv Mater, 2021, 33: e2100701. DOI: 10.1002/adma.202100701
[55] Wang J, Tang W, Yang M, et al. Inflammatory tumor microenvironment responsive neutrophil exosomes-based drug delivery system for targeted glioma therapy[J]. Biomaterials, 2021, 273: 120784. DOI: 10.1016/j.biomaterials.2021.120784
[56] Zhang J, Chen C, Li A, et al. Immunostimulant hydrogel for the inhibition of malignant glioma relapse post-resection[J]. Nat Nanotechnol, 2021, 16: 538-548. DOI: 10.1038/s41565-020-00843-7
[57] Niu W, Xiao Q, Wang X, et al. A Biomimetic Drug Delivery System by Integrating Grapefruit Extracellular Vesicles and Doxorubicin-Loaded Heparin-Based Nanoparticles for Glioma Therapy[J]. Nano Lett, 2021, 21: 1484-1492. DOI: 10.1021/acs.nanolett.0c04753
[58] Liu Y, Wang X, Li J, et al. Sphingosine 1-Phosphate Liposomes for Targeted Nitric Oxide Delivery to Mediate Anticancer Effects against Brain Glioma Tumors[J]. Adv Mater, 2021, 33: e2101701. DOI: 10.1002/adma.202101701
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