NUF2在食管癌中的作用及临床意义
The role and clinical significance of NUF2 in esophageal cancer
基于TCGA、GEO的数据库整合分析，相较于癌旁组织，NUF2的mRNA及蛋白表达水平在食管鳞状细胞癌、食管腺癌及小细胞食管癌中均显著上调，且在食管鳞状细胞癌中的表达水平高于食管腺癌[17, 18]。进一步的亚型分析显示，在小细胞食管癌中，NUF2的表达上调最为显著；经qRT-PCR验证，NUF2可作为该亚型的特征性分子标志物[19]。在食管鳞状细胞癌中，多因素分析证实NUF2的高表达是一个独立的预后不良指标，NUF2高表达患者的总生存期（OS）和无复发生存期（RFS）显著缩短[20]。另有研究表明，当NUF2与LY6K(lymphocyte antigen 6 complex locus K淋巴细胞抗原 6 复合物基因座 K)联合表达时，患者预后更差，复发率更高[20]，提示NUF2作为联合预后标志物的临床价值。
Integrated analysis based on TCGA and GEO databases revealed that compared to adjacent normal tissues, the mRNA and protein expression levels of NUF2 were significantly upregulated in esophageal squamous cell carcinoma, esophageal adenocarcinoma, and small cell esophageal cancer, with higher expression levels observed in esophageal squamous cell carcinoma than in esophageal adenocarcinoma [17, 18]. Further subtype analysis indicated that NUF2 upregulation was most pronounced in small cell esophageal cancer, and qRT-PCR validation confirmed NUF2 as a characteristic molecular marker for this subtype [19]. In esophageal squamous cell carcinoma, multivariate analysis demonstrated that high NUF2 expression is an independent indicator of poor prognosis, with patients exhibiting high NUF2 expression showing significantly shorter overall survival (OS) and recurrence-free survival (RFS) [20]. Another study suggested that when NUF2 is co-expressed with LY6K (lymphocyte antigen 6 complex locus K), patients experience worse prognosis and higher recurrence rates [20], highlighting the clinical value of NUF2 as a combined prognostic marker.
Zheng等进行了NUF2表达水平与食管癌肿瘤微环境中免疫浸润（immune infiltration）相关性研究结果表明，NUF2表达水平与肿瘤纯度（tumor purity）呈显著正相关，与树突状细胞浸润（infiltration of dendritic cells）呈显著负相[18]。
Zheng et al. investigated the correlation between NUF2 expression levels and immune infiltration in the tumor microenvironment of esophageal cancer. Their results showed that NUF2 expression levels were significantly positively correlated with tumor purity and significantly negatively correlated with the infiltration of dendritic cells [18].
在诊疗价值方面，NUF2展现出作为新型诊断标志物的潜力。食管鳞状细胞癌中枢纽基因的 ROC 分析显示NUF2 （AUC= 99.2%），表明NUF2可高效区分癌组织与正常组织[18]。此外，在一项针对 HLA-A*24:02 阳性（HLA-A*24:02-positive）食管癌患者的多肽疫苗 S-588410 的 I/II 期临床试验(UMIN000023324)中，NUF2 被确认为一种能引发肽特异性细胞毒性 T 淋巴细胞（CTL）反应的关键癌-睾丸抗原;该疫苗显著增强了肿瘤内浸润的 CD8+T 细胞，并上调了肿瘤微环境中 PD-L1 的表达，这表明其与免疫检查点抑制剂具有协同作用潜力[21]。
In terms of diagnostic and therapeutic value, NUF2 demonstrates potential as a novel diagnostic marker. ROC analysis of hub genes in esophageal squamous cell carcinoma revealed that NUF2 (AUC = 99.2%) can effectively distinguish cancerous tissues from normal tissues [18]. Additionally, in a phase I/II clinical trial (UMIN000023324) evaluating the peptide vaccine S-588410 for HLA-A*24:02-positive esophageal cancer patients, NUF2 was identified as a key cancer-testis antigen capable of eliciting peptide-specific cytotoxic T lymphocyte (CTL) responses. The vaccine significantly enhanced intratumoral infiltration of CD8+ T cells and upregulated PD-L1 expression in the tumor microenvironment, suggesting its potential synergistic effects with immune checkpoint inhibitors [21].
NUF2在胃癌中的作用及临床意义
The role and clinical significance of NUF2 in gastric cancer
NUF2在胃癌组织中的异常高表达已在多项研究中得到一致验证。Kaneko和Ohnuma的研究分别检测了14例和10例胃癌组织样本，结果表明，与正常胃黏膜组织相比，胃癌组织中NUF2的mRNA及蛋白表达水平显著上调[12, 22]。在临床病理关联性方面，NUF2的表达水平与TNM分期进展（III/IV期高于I/II期）、淋巴结转移及T分期（原文：进一步分析显
Abnormal overexpression of NUF2 in gastric cancer tissues has been consistently validated in multiple studies. Research by Kaneko and Ohnuma examined 14 and 10 gastric cancer tissue samples respectively, demonstrating that both mRNA and protein expression levels of NUF2 were significantly upregulated in gastric cancer tissues compared to normal gastric mucosa [12, 22]. Regarding clinicopathological correlations, NUF2 expression levels were associated with TNM stage progression (higher in stages III/IV than I/II), lymph node metastasis, and T stage (further analysis showed...
示NUF2表达与胃癌的TNM分期（P=0.023）、淋巴结转移（P=0.01）、
The expression of NUF2 was associated with TNM stage (P=0.023) and lymph node metastasis (P=0.01) in gastric cancer.
T 分期（P=0.036）密切相关）显著正相关，提示NUF2在肿瘤进展中可能发挥推动作用[23]。多项研究也证实，NUF2高表达患者的总体生存期（OS）和无进展生存期（PFS）均显著缩短[24]，表明NUF2可能通过促进肿瘤复发和转移影响疾病进展。多因素Cox回归进一步证实，NUF2高表达是胃癌患者总生存期（OS）和无复发生存期（RFS）的独立危险因素[25]。此外，术后随访数据表明，NUF2低表达胃癌患者更易发生肿瘤复发，且在弥漫型、Her2阴性及局部淋巴结阳性亚组中，NUF2高表达者的预后劣势更为突出[16]。
T stage (P=0.036) showed a significant positive correlation, suggesting that NUF2 may play a promoting role in tumor progression [23]. Multiple studies have also confirmed that patients with high NUF2 expression had significantly shorter overall survival (OS) and progression-free survival (PFS) [24], indicating that NUF2 may influence disease progression by promoting tumor recurrence and metastasis. Multivariate Cox regression further confirmed that high NUF2 expression is an independent risk factor for overall survival (OS) and recurrence-free survival (RFS) in gastric cancer patients [25]. Additionally, postoperative follow-up data revealed that gastric cancer patients with low NUF2 expression were more prone to tumor recurrence, and the prognostic disadvantage was more pronounced in high NUF2 expressers within the diffuse-type, Her2-negative, and locally lymph node-positive subgroups [16].
Ge等研究NUF2表达水平与胃癌肿瘤微环境中免疫浸润相关性结果表明，NUF2高表达与胃癌组织中巨噬细胞、中性、B细胞、CD4+ T细及CD8+ T细胞浸润水平呈显著负相关[16]，提示NUF2可能通过抑制抗肿瘤免疫反应促进肿瘤进展。Lu等的多组学分析进一步验证，NUF2表达与CD8+ T细胞（P<0.05）、巨噬细胞（P=0.002）及树突状细胞（P=0.016）浸润呈负相关，且这种负相关性在弥漫型胃癌中更为显著（r=-0.478, P<0.001）[26]。
Ge et al.'s study on the correlation between NUF2 expression levels and immune infiltration in the tumor microenvironment of gastric cancer showed that high NUF2 expression was significantly negatively correlated with the infiltration levels of macrophages, neutrophils, B cells, CD4+ T cells, and CD8+ T cells in gastric cancer tissues [16], suggesting that NUF2 may promote tumor progression by suppressing anti-tumor immune responses. Lu et al.'s multi-omics analysis further confirmed that NUF2 expression was negatively correlated with the infiltration of CD8+ T cells (P<0.05), macrophages (P=0.002), and dendritic cells (P=0.016), and this negative correlation was more pronounced in diffuse-type gastric cancer (r=-0.478, P<0.001) [26].
基于NUF2表达量与患者预后的相关性，NUF2可作为标志物用于胃癌的诊断与治疗。作为非侵入性诊断标志物，NUF2的mRNA水平在胃癌患者血浆中显著升高，且与循环肿瘤细胞（CTC）检出率呈强正相关，提示NUF2通过液体活检辅助胃癌早期筛查的潜在价值[24]。治疗层面，NUF2被证实为潜在治疗靶点。靶向NUF2的小分子抑制剂（如槲皮素）在体内外实验中均显著抑制肿瘤生长，且毒性较低[24]。
Based on the correlation between NUF2 expression levels and patient prognosis, NUF2 can serve as a biomarker for the diagnosis and treatment of gastric cancer. As a non-invasive diagnostic marker, the mRNA level of NUF2 is significantly elevated in the plasma of gastric cancer patients and shows a strong positive correlation with the detection rate of circulating tumor cells (CTC), indicating the potential value of NUF2 in aiding early gastric cancer screening through liquid biopsy [24]. In terms of treatment, NUF2 has been identified as a potential therapeutic target. Small-molecule inhibitors targeting NUF2 (such as quercetin) significantly inhibit tumor growth in both in vitro and in vivo experiments, with low toxicity [24].
NUF2在肝癌中的作用及临床意义
The Role and Clinical Significance of NUF2 in Liver Cancer
基于TCGA 数据库分析，NUF2在肝癌中表达上调[27, 28]，其在HBV相关肝癌[29]，HCV相关肝癌[30]和肝癌转移潜能细胞系[31]中也高表达。Liu [8]和Gu[32]的研究通过体内实验进一步验证了NUF2在肝癌组织中mRNA及蛋白质表达水平显著高于正常组织。NUF2的表达水平与肿瘤病理分期[33]和肝细胞肝癌组织的微卫星不稳定[34]存在正相关。根据TCGA数据库描绘的Kaplan-Meier生存分析曲线显示，NUF2高表达组中肝细胞癌患者总生存期（OS）和无进展生存期（DFS）显著缩短[8, 28, 35]。NUF2 已被证实可为肝癌患者提供独立预后因素[32]。
Analysis based on the TCGA database reveals that NUF2 is upregulated in liver cancer [27, 28], and it is also highly expressed in HBV-related liver cancer [29], HCV-related liver cancer [30], and liver cancer cell lines with metastatic potential [31]. Studies by Liu [8] and Gu [32] further validated through in vivo experiments that the mRNA and protein expression levels of NUF2 in liver cancer tissues are significantly higher than in normal tissues. The expression level of NUF2 is positively correlated with tumor pathological staging [33] and microsatellite instability in hepatocellular carcinoma tissues [34]. Kaplan-Meier survival analysis curves derived from the TCGA database show that hepatocellular carcinoma patients in the high NUF2 expression group have significantly shorter overall survival (OS) and disease-free survival (DFS) [8, 28, 35]. NUF2 has been confirmed as an independent prognostic factor for liver cancer patients [32].
在NUF2表达水平与肝癌肿瘤微环境中免疫浸润的相关性分析中，Wang等通过多组学分析发现，NUF2高表达与肝癌组织中B细胞、髓样树突状细、中性粒细及CD4+ T细胞浸润水平呈正相关，提示其可能通过重塑免疫微环境促进肿瘤进展[34]。
In the analysis of the correlation between NUF2 expression levels and immune infiltration in the tumor microenvironment of liver cancer, Wang et al. discovered through multi-omics analysis that high NUF2 expression is positively correlated with the infiltration levels of B cells, myeloid dendritic cells, neutrophils, and CD4+ T cells in liver cancer tissues, suggesting that NUF2 may promote tumor progression by remodeling the immune microenvironment [34].
在肝癌的临床诊疗方面，NUF2展现出较好的应用前景。Wang等[34]研究指出，NUF2在肝癌细胞系比正常肝细胞表达升高，与健康对照组相比，肝癌患者的癌组织和血液中NUF2的表达水平升高，手术治疗后，肝癌患者的血液中NUF2的表达水平下降。 NUF2联合肝硬化程度（NUF2 and liver cirrhosis in combination）检测可将早期复发检出的曲线下面积（AUC）从0.75提升至0.85，显著提高肝细胞癌早期复发检出率[27]。在基于随机森林算法构建的预后模型中，NUF2被鉴定为5个核心生物标志物之一，联合SPC25、MCM2、BLM、AURKA的风险评分可显著区分肝癌高危患者（p<0.001）[32]。
NUF2 demonstrates promising clinical applications in the diagnosis and treatment of liver cancer. Wang et al. [34] found that NUF2 expression is elevated in liver cancer cell lines compared to normal hepatocytes. Compared to healthy controls, NUF2 levels are higher in both tumor tissues and blood samples of liver cancer patients, and these levels decrease post-surgery. Combining NUF2 with liver cirrhosis assessment (NUF2 and liver cirrhosis in combination) improves the area under the curve (AUC) for early recurrence detection from 0.75 to 0.85, significantly enhancing the detection rate of early hepatocellular carcinoma recurrence [27]. In a prognostic model based on a random forest algorithm, NUF2 was identified as one of five core biomarkers. When combined with SPC25, MCM2, BLM, and AURKA, the risk score effectively distinguishes high-risk liver cancer patients (p < 0.001) [32].
NUF2高表达与肿瘤突变负荷（TMB）[34]及免疫检查点基因（PD-L1、CTLA4）[36]呈正相关，提示其对免疫检查点抑制剂的潜在敏感性。NUF2作为NDC80复合物核心组分的特性，为AURKA/CDK1抑制剂联合治疗肝癌方案提供了理论依据[33]。
High NUF2 expression is positively correlated with tumor mutational burden (TMB) [34] and immune checkpoint genes (PD-L1, CTLA4) [36], suggesting potential sensitivity to immune checkpoint inhibitors. As a core component of the NDC80 complex, NUF2 provides a theoretical basis for combination therapy with AURKA/CDK1 inhibitors in liver cancer treatment [33].
NUF2在胆管癌中的作用及临床意义
The Role and Clinical Significance of NUF2 in Cholangiocarcinoma
最新研究表明，与正常胆道上皮细胞相比，人胆管癌 细胞系 QBC939 、 RBE 和 HCCC-9810 中 NUF2 的表达显著升高，QBC939 最为明显 [14]。NUF2高表达与胆管癌患者临床晚期TNM分期、淋巴结转移及血管侵犯呈显著正相关，且高表达组患者淋巴转移、肿瘤大小>5cm及血管浸润的比例显著高于低表达组[14]。日本原发性肝癌多组学队列（含34例肝内胆管癌）的基因组分析显示，NUF2在肝内胆管癌中存在一定频率的基因组扩增（3.2%），尽管研究未单独解析胆管癌亚组，但NUF2的扩增特征和预后关联为胆管肿瘤的分子分型及治疗靶点探索提供了间接证据[37]。
Recent studies indicate that NUF2 expression is significantly higher in human cholangiocarcinoma cell lines (QBC939, RBE, and HCCC-9810) compared to normal biliary epithelial cells, with QBC939 showing the most pronounced increase [14]. High NUF2 expression is strongly associated with advanced TNM staging, lymph node metastasis, and vascular invasion in cholangiocarcinoma patients. Patients with high NUF2 expression exhibit significantly higher rates of lymph node metastasis, tumor size >5 cm, and vascular infiltration compared to the low-expression group [14]. Genomic analysis of a Japanese multi-omics cohort of primary liver cancer (including 34 intrahepatic cholangiocarcinoma cases) revealed a certain frequency of NUF2 genomic amplification (3.2%) in intrahepatic cholangiocarcinoma. Although the study did not separately analyze the cholangiocarcinoma subgroup, the amplification characteristics and prognostic associations of NUF2 provide indirect evidence for molecular subtyping and therapeutic target exploration in biliary tumors [37].
NUF2高表达与胆管癌患者不良生存结局显著相关。多因素Cox回归分析证实NUF2是胆管癌患者总生存期（OS）的独立危险因素，Kaplan-Meier生存曲线显示其高表达组总生存期显著缩短[14]。值得注意的是，基于GDSC数据库的化疗敏感性预测表明，NUF2高表达胆管癌对5-氟尿嘧啶和奥沙利铂敏感性增强，提示其作为化疗疗效预测标志物的潜力[38] 。
High expression of NUF2 is significantly associated with poor survival outcomes in cholangiocarcinoma patients. Multivariate Cox regression analysis confirmed that NUF2 is an independent risk factor for overall survival (OS) in cholangiocarcinoma patients, and Kaplan-Meier survival curves showed significantly shorter OS in the high-expression group [14]. Notably, chemotherapy sensitivity predictions based on the GDSC database indicate that cholangiocarcinoma with high NUF2 expression exhibits increased sensitivity to 5-fluorouracil and oxaliplatin, suggesting its potential as a predictive biomarker for chemotherapy efficacy [38].
NUF2在胆囊癌中的作用及临床意义
The Role and Clinical Significance of NUF2 in Gallbladder Cancer
NUF2在胆囊癌中呈现显著异常高表达已被实验证实。Gao等研究了5对胆囊腺癌组织和癌旁组织中NUF2的表达量，结果表明胆囊腺癌组织NUF2 表达水平较癌旁组织升高[15]。尽管目前尚未开展NUF2靶向治疗的体内实验，但NUF2体外抑制肿瘤生长的效应（如敲低NUF2显著抑制胆囊癌细胞增殖及集落形成）表明NUF2有望成为治疗胆囊癌的潜在靶点[15]。
Experimental evidence has confirmed the significantly abnormal high expression of NUF2 in gallbladder cancer. Gao et al. investigated the expression levels of NUF2 in five pairs of gallbladder adenocarcinoma tissues and adjacent normal tissues, revealing that NUF2 expression was elevated in gallbladder adenocarcinoma tissues compared to adjacent tissues [15]. Although in vivo experiments targeting NUF2 have not yet been conducted, the tumor-suppressive effects of NUF2 inhibition in vitro (e.g., knockdown of NUF2 significantly suppresses gallbladder cancer cell proliferation and colony formation) suggest that NUF2 holds promise as a potential therapeutic target for gallbladder cancer [15].
一项纳入9例不可切除、标准化疗耐药的晚期胆道癌患者的I期临床试验(UMIN000003229)结果显示，包含NUF2的三肽疫苗耐受性良好，未观察到3/4级不良反应，证实了其安全性；所有患者均诱导出针对NUF2的特异性T细胞免疫反应，明确了其显著的免疫原性；临床疗效方面，5例患者获得稳定疾病（stable disease, SD），中位总生存期（overall survival, OS）达9.7个月，优于同期标准化疗耐药患者的预期生存期（通常＜6个月），进一步验证了NUF2作为胆道癌免疫治疗靶点的可行性；此外，2级注射部位反应及疾病进展（progressive disease, PD）后继续接种与更长的OS相关，间接提示针对NUF2的持续免疫刺激可能与患者预后改善相关[39]。
A Phase I clinical trial (UMIN000003229) involving nine patients with unresectable, chemotherapy-resistant advanced biliary tract cancer demonstrated that a tripeptide vaccine containing NUF2 was well-tolerated, with no grade 3/4 adverse events observed, confirming its safety. All patients developed NUF2-specific T-cell immune responses, highlighting its significant immunogenicity. In terms of clinical efficacy, five patients achieved stable disease (SD), with a median overall survival (OS) of 9.7 months, surpassing the expected survival of chemotherapy-resistant patients (typically <6 months), further validating the feasibility of NUF2 as an immunotherapy target for biliary tract cancer. Additionally, grade 2 injection site reactions and continued vaccination after disease progression (PD) were associated with longer OS, indirectly suggesting that sustained immune stimulation targeting NUF2 may correlate with improved patient outcomes [39].
NUF2在胰腺癌中的作用及临床意义
The Role and Clinical Significance of NUF2 in Pancreatic Cancer
两项体外研究指出，NUF2 mRNA及蛋白水平在胰腺癌组织和细胞系（Sw1990、PANC-1、BXPC-3 和 MLA-PACA-2）中显著高表达，尤其PANC-1 细胞系最为明显[40, 41]。胰腺导管腺癌细胞和原发性肿瘤的分析显示NUF2在胰腺导管腺癌中上调[42]。在胰腺癌中，NUF2的表达水平随肿瘤分期进展而增加，且其高表达与总生存期（OS）缩短显著相关，证实了NUF2是患者预后不良的危险因素[43] 。基于CDCA家族风险评分构建的预后模型在TCGA-PAAD队列和ICGC-PACA队列中验证了NUF2对胰腺腺癌患者预后的预测价值，结果表明，NUF2是构成该风险模型的关键风险因子之一[43]。
Two in vitro studies indicated that NUF2 mRNA and protein levels were significantly overexpressed in pancreatic cancer tissues and cell lines (Sw1990, PANC-1, BXPC-3, and MLA-PACA-2), with the PANC-1 cell line showing the most pronounced expression [40, 41]. Analysis of pancreatic ductal adenocarcinoma cells and primary tumors revealed that NUF2 is upregulated in pancreatic ductal adenocarcinoma [42]. In pancreatic cancer, NUF2 expression levels increase with tumor stage progression, and its high expression is significantly associated with shorter overall survival (OS), confirming NUF2 as a risk factor for poor patient prognosis [43]. A prognostic model based on the CDCA family risk score validated the predictive value of NUF2 for pancreatic adenocarcinoma patient outcomes in both the TCGA-PAAD and ICGC-PACA cohorts, demonstrating that NUF2 is one of the key risk factors in this model [43].
晚期胰腺癌患者的I期临床试验（UMIN000004337）将NUF2肽段纳入多靶点疫苗（联合KIF20A、VEGFR1/2肽段），结果显示该疫苗安全性好，所有9例标准治疗失败的晚期患者均未出现≥3级不良反应，疫苗成功诱导患者产生NUF2特异性T细胞应答，其中4例观察到疾病控制（SD/PD缓解，中位PFS达90天，OS达207天），提示NUF2靶向免疫治疗具有潜在临床获益[44]。
A Phase I clinical trial (UMIN000004337) for advanced pancreatic cancer patients incorporated NUF2 peptides into a multi-target vaccine (combined with KIF20A and VEGFR1/2 peptides). The results showed that the vaccine was well-tolerated, with no grade ≥3 adverse events observed in all nine advanced patients who had failed standard treatment. The vaccine successfully induced NUF2-specific T-cell responses, and disease control (SD/PD response) was observed in four cases, with a median progression-free survival (PFS) of 90 days and OS of 207 days, suggesting potential clinical benefits of NUF2-targeted immunotherapy [44].
NUF2在结直肠癌中的作用及临床意义
The Role and Clinical Significance of NUF2 in Colorectal Cancer
TCGA和GEO数据联合分析证实NUF2 表达量在结直肠癌中特异性上调[45, 46]。此外，Zhu等人（2019）基于直肠腺癌组织的RNA测序及生物信息学分析研究表明，NUF2 mRNA 在直肠腺癌中高表达，NUF2是直肠腺癌特异性 PPI 网络的枢纽蛋白[47]。Kobayashi等基于442例结直肠癌患者组织样本的研究进一步表明，NUF2在结直肠癌组织中的mRNA和蛋白表达水平显著高于癌旁组织，且NUF2的高表达是结直肠癌患者的独立预后因素，与 NUF2低表达患者相比，NUF2高表达的结直肠癌患者生存期较短[48]
Joint analysis of TCGA and GEO data confirmed that NUF2 expression is specifically upregulated in colorectal cancer [45, 46]. Additionally, Zhu et al. (2019) demonstrated through RNA sequencing and bioinformatics analysis of rectal adenocarcinoma tissues that NUF2 mRNA is highly expressed in rectal adenocarcinoma, and NUF2 serves as a hub protein in the rectal adenocarcinoma-specific PPI network [47]. Kobayashi et al.'s study, based on tissue samples from 442 colorectal cancer patients, further revealed that both mRNA and protein expression levels of NUF2 are significantly higher in colorectal cancer tissues compared to adjacent normal tissues. Moreover, high NUF2 expression is an independent prognostic factor for colorectal cancer patients, with those exhibiting high NUF2 expression having shorter survival periods compared to patients with low NUF2 expression [48]..
3. NUF2在消化道癌症发生发展中的作用机制
3. The Role of NUF2 in the Development and Progression of Gastrointestinal Cancers
多项研究表明，靶向NUF2在消化道肿瘤治疗中具有重要作用，其作用机制涉及多个关键信号通路的调控。下面将对NUF2在消化道癌症发生发展中的作用机制进行阐述。
Multiple studies have shown that targeting NUF2 plays a crucial role in the treatment of gastrointestinal tumors, with its mechanisms involving the regulation of several key signaling pathways. Below, the role of NUF2 in the development and progression of gastrointestinal cancers will be elaborated.
NUF2调控基因组不稳定性
NUF2 Regulates Genomic Instability
无限增殖是癌细胞的核心特征之一，通过干扰细胞周期和抑制细胞分裂，抗肿瘤药物能够有效地控制肿瘤的生长和扩散。作为NDC80复合物的关键组分，NUF2通过NDC80复合物稳定微管-着丝粒连接，激活纺锤体检查点（SAC），确保染色体精确分离[4, 49-52]。有缺陷的染色体在有丝分裂期间会导致基因组不稳定性，该缺陷包括纺锤体组装、检查点功能障碍和有丝分裂纺锤体缺陷，这是肿瘤进展的一个重要特征[53]。在原发性小细胞食管癌中，NUF2的mRNA高表达与DNA拷贝数增益显著正相关，功能富集分析表明，NUF2高表达富集于细胞周期核心通路，包括有丝分裂纺锤体组、DNA复制修复及p53/RB信号通路[19]。结合Liu等对小细胞食管癌分子特征的比较研究，NUF2可能通过协同调控染色体分离保真度与DNA修复，驱动小细胞食管癌的基因组不稳定性[17]。结直肠癌研究显示，NUF2 与 hnRNP K 结合后上调，通过调控中期染色体排列参与有丝分裂，而敲低 NUF2 可导致 HCT116、HT29 等结肠癌细胞染色体排列失败，印证其在维持基因组稳定中的关键作用[54]。此外，Hu等的实验研究发现NUF2正向调控长链非编码RNA AF339813，上调Cyclin D1和CDK4/CDK6 蛋白表达，加速G1/S期转换，促进胰腺癌细胞增殖[41]。最新研究指出，在胃癌中，NUF2缺失诱导G2/M期阻滞，伴随Cyclin B1/CDK1复合物表达下调，破坏动粒-微管连接，导致染色体错误分离并加剧基因组不稳定性（CIN）[24]。Liu等的体内外实验指出，在肝癌中，慢病毒介导的NUF2沉默可抑制HepG2细胞增殖并引起G2/M 期细胞周期阻滞，在分子机制上，NUF2通过调控细胞周期蛋白（cyclin B1/Cdc25A/Cdc2）表达推动肝癌进展[55]。上述研究进一步证实了NUF2在基因组稳定性调控的核心地位。
Unlimited proliferation is one of the core characteristics of cancer cells. By interfering with the cell cycle and inhibiting cell division, antitumor drugs can effectively control tumor growth and spread. As a key component of the NDC80 complex, NUF2 stabilizes the microtubule-kinetochore connection through the NDC80 complex, activates the spindle assembly checkpoint (SAC), and ensures accurate chromosome segregation [4, 49-52]. Defective chromosomes during mitosis can lead to genomic instability, which includes spindle assembly defects, checkpoint dysfunction, and mitotic spindle abnormalities—a hallmark of tumor progression [53]. In primary small cell esophageal cancer, high mRNA expression of NUF2 is significantly positively correlated with DNA copy number gain. Functional enrichment analysis indicates that high NUF2 expression is enriched in core cell cycle pathways, including mitotic spindle assembly, DNA replication and repair, and the p53/RB signaling pathway [19]. Combined with Liu et al.'s comparative study on the molecular characteristics of small cell esophageal cancer, NUF2 may drive genomic instability in small cell esophageal cancer by coordinately regulating chromosome segregation fidelity and DNA repair [17]. Studies in colorectal cancer show that NUF2 is upregulated upon binding with hnRNP K and participates in mitosis by regulating metaphase chromosome alignment. Knockdown of NUF2 leads to chromosome misalignment in colon cancer cells such as HCT116 and HT29, confirming its critical role in maintaining genomic stability [54]. Additionally, Hu et al.'s experimental research found that NUF2 positively regulates the long non-coding RNA AF339813, upregulates Cyclin D1 and CDK4/CDK6 protein expression, accelerates the G1/S phase transition, and promotes pancreatic cancer cell proliferation [41]. The latest research indicates that in gastric cancer, NUF2 deletion induces G2/M phase arrest, accompanied by downregulation of Cyclin B1/CDK1 complex expression, disrupts kinetochore-microtubule connections, and leads to chromosome missegregation, exacerbating chromosomal instability (CIN) [24]. Liu et al.'s in vitro and in vivo experiments demonstrate that in liver cancer, lentivirus-mediated NUF2 silencing inhibits HepG2 cell proliferation and causes G2/M phase cell cycle arrest. Mechanistically, NUF2 drives liver cancer progression by regulating the expression of cell cycle proteins (cyclin B1/Cdc25A/Cdc2) [55]. These studies further confirm the central role of NUF2 in the regulation of genomic stability.
NUF2诱导细胞凋亡
NUF2 induces apoptosis
细胞凋亡异常是癌症发生发展的关键特征之一，靶向凋亡通路的关键调控分子以恢复肿瘤细胞凋亡敏感性，是开发抗癌药物的重要策略。在胃癌的体内外研究中，NUF2通过上调BCL-2家族抗凋亡蛋白（BCL-XL），抑制促凋亡因子（BAX/BAK），提高p-ERK和p-MEK的表达水平，激活MAPK通路，降低线粒体膜通透性，从而抑制细胞凋亡[24]；NUF2耗竭时，BAX 蛋白水平增加，BCL-2 水平降低，p-ERK和p-MEK的表达降低，促进细胞凋亡[24]。在食管鳞癌中，NUF2敲低后，细胞凋亡率显著增加，NUF2通过c-MYC/Snail轴调控细胞凋亡[56]。在肝癌中，NUF2通过稳定ERBB3蛋白抑制其泛素化降解，激活PI3K/AKT通路，上调抗凋亡因子BCL-2/BCL-XL并抑制BAX易位，最终阻断caspase-3活化[55]。胆管癌的体内外实验证实，NUF2通过抑制p62介导的TFR1自噬性降解，激活p38/MAPK信号通路驱动肿瘤进展，当敲低NUF2后，p-p38 和 p-ERK的表达下调，MAPK通路被抑制，LC3B 蛋白水平升高，p62 蛋白水平降低，促进自噬，并以p62依赖性方式促进TFR1自噬降解，进而诱导细胞凋亡[14]。在胰腺癌中，NUF2 过表达通过上调 lncRNA AF339813，降低 Caspase-3/9 和Bax 的表达，促进Bcl-2表达，从而抑制细胞凋亡[41]。在结直肠癌中，敲低NUF2诱导结直肠癌细胞系（X-1、HCT8、HT-29、LS180、SW1116、SW48、SW620 、 SW948 、HCT15、KM12c、SW480、DLD-1、RKO、WiDr-Tc）的细胞凋亡，具体通路未知[12]。
Abnormal apoptosis is one of the key features of cancer development, and targeting key regulatory molecules in the apoptotic pathway to restore the sensitivity of tumor cells to apoptosis is an important strategy for developing anticancer drugs. In in vitro and in vivo studies of gastric cancer, NUF2 inhibits apoptosis by upregulating the anti-apoptotic protein BCL-XL of the BCL-2 family, suppressing pro-apoptotic factors (BAX/BAK), increasing the expression levels of p-ERK and p-MEK, activating the MAPK pathway, and reducing mitochondrial membrane permeability [24]. When NUF2 is depleted, BAX protein levels increase, BCL-2 levels decrease, and the expression of p-ERK and p-MEK is reduced, promoting apoptosis [24]. In esophageal squamous cell carcinoma, after NUF2 knockdown, the apoptosis rate significantly increases, and NUF2 regulates apoptosis through the c-MYC/Snail axis [56]. In liver cancer, NUF2 inhibits ubiquitination degradation by stabilizing ERBB3 protein, activates the PI3K/AKT pathway, upregulates anti-apoptotic factors BCL-2/BCL-XL, and suppresses BAX translocation, ultimately blocking caspase-3 activation [55]. In vitro and in vivo experiments in cholangiocarcinoma confirm that NUF2 drives tumor progression by inhibiting p62-mediated TFR1 autophagic degradation and activating the p38/MAPK signaling pathway. When NUF2 is knocked down, the expression of p-p38 and p-ERK decreases, the MAPK pathway is inhibited, LC3B protein levels rise, p62 protein levels decline, promoting autophagy and inducing TFR1 autophagic degradation in a p62-dependent manner, thereby triggering apoptosis [14]. In pancreatic cancer, NUF2 overexpression inhibits apoptosis by upregulating lncRNA AF339813, reducing the expression of Caspase-3/9 and Bax, and promoting Bcl-2 expression [41]. In colorectal cancer, NUF2 knockdown induces apoptosis in colorectal cancer cell lines (X-1, HCT8, HT-29, LS180, SW1116, SW48, SW620, SW948, HCT15, KM12c, SW480, DLD-1, RKO, WiDr-Tc), though the specific pathway remains unknown [12].
NUF2促进细胞迁移和侵袭
NUF2 promotes cell migration and invasion
细胞迁移（migration）和侵袭（invasion）是癌细胞的主要恶性生物学行为之一，更是导致临床治疗失败和患者预后不良的重要因素。NUF2通过重塑细胞骨架和调控上皮-间充质转化（EMT）相关通路增强肿瘤细胞的迁移与侵袭能力。在胆囊癌中，NUF2过表达显著诱导波形蛋白（Vimentin）、N-钙粘蛋白（N-cadherin）及Snail上调，同时抑制E-钙粘蛋白表达，促进EMT进程[15]。在食管鳞状细胞癌中，NUF2通过转录激活Snail锌指蛋白，上调基质金属蛋白酶MMP-2/MMP-9，增强基底膜降解能力[56]。在胆管癌中，NUF2通过抑制TFR1的自噬降解，激活p38/MAPK通路，进一步促进细胞迁移与侵袭能力，NUF2敲低后胆管癌细胞迁移率和侵袭细胞数降低[14]。在胃癌中，沉默NUF2可抑制胃癌细胞系（AGS和HGC-27）中的肿瘤的迁移与侵袭[24]。在胰腺导管腺癌中，circFOXK2-YBX1-hnRNPK转录调控轴可特异性上调NUF2表达，促进胰腺导管腺癌细胞侵袭[42]。在肝癌中，沉默 NUF2 可显著降低肝癌HCCLM3 细胞的迁移和侵袭能力，尽管具体通路未明确，但由此可知NUF2通过促进细胞运动性驱动肝癌进展[57]。
Cell migration and invasion are among the primary malignant biological behaviors of cancer cells and represent critical factors contributing to clinical treatment failure and poor patient prognosis. NUF2 enhances tumor cell migration and invasion by remodeling the cytoskeleton and regulating pathways associated with epithelial-mesenchymal transition (EMT). In gallbladder cancer, NUF2 overexpression significantly induces the upregulation of vimentin, N-cadherin, and Snail while suppressing E-cadherin expression, thereby promoting the EMT process [15]. In esophageal squamous cell carcinoma, NUF2 transcriptionally activates the zinc finger protein Snail, upregulates matrix metalloproteinases MMP-2/MMP-9, and enhances basement membrane degradation capacity [56]. In cholangiocarcinoma, NUF2 inhibits autophagic degradation of TFR1, activates the p38/MAPK pathway, and further promotes cell migration and invasion. Knockdown of NUF2 reduces the migration rate and number of invasive cholangiocarcinoma cells [14]. In gastric cancer, silencing NUF2 inhibits tumor migration and invasion in gastric cancer cell lines (AGS and HGC-27) [24]. In pancreatic ductal adenocarcinoma, the circFOXK2-YBX1-hnRNPK transcriptional regulatory axis specifically upregulates NUF2 expression, promoting pancreatic ductal adenocarcinoma cell invasion [42]. In liver cancer, silencing NUF2 significantly reduces the migration and invasion capabilities of HCCLM3 cells. Although the specific pathway remains unclear, these findings suggest that NUF2 drives liver cancer progression by enhancing cell motility [57].
NUF2重塑肿瘤免疫微环境
NUF2 Remodels the Tumor Immune Microenvironment
肿瘤微环境（TME）作为肿瘤发生发展的关键调控枢纽，其组成和功能状态直接影响肿瘤的免疫逃逸、治疗响应及临床预后。NUF2通过调控肿瘤微环境中免疫细胞浸润、功能状态及免疫抑制性分子表达，系统性介导免疫逃逸及肿瘤进展。
The tumor microenvironment (TME), as a key regulatory hub in tumorigenesis and progression, directly influences immune evasion, treatment response, and clinical outcomes through its composition and functional state. NUF2 systematically mediates immune evasion and tumor progression by regulating immune cell infiltration, functional states, and the expression of immunosuppressive molecules within the tumor microenvironment.
NUF2通过抑制抗肿瘤免疫细胞浸润削弱抗肿瘤免疫应答。研究表明，NUF2高表达与多种消化道癌症中CD8+ T细胞、树突状细胞（DC）及自然杀伤细胞（NK）浸润减少显著相关。食管鳞癌中，NUF2 的表达水平与肿瘤纯度呈显著正相关，而与树突状细胞的浸润呈显著负相关，说明NUF2可能通过抑制抗肿瘤免疫微环境促进食管鳞癌进展[18]。TIMER 数据库研究发现，在胃癌中，NUF2转录水平与高免疫细胞浸润（巨噬细胞，中性粒细胞，B 细胞浸润，CD4 + T 细胞，CD8 + T 细胞，树突状细胞）之间存在显著的负相关，提示NUF2可能抑制抗肿瘤免疫应答[16, 26]。在肝癌中，NUF2表达量与CD8⁺T细胞、调节性T细胞浸润显著相关，同样提示NUF2可能通过抑制抗肿瘤免疫促进肝癌进展[36]。Wang等的研究进一步指出肝癌组织中NUF2 mRNA水平与CD8+细胞毒性T细胞（CTLs）的浸润密度呈负相关，而与M2型肿瘤相关巨噬细胞（TAMs）的比例呈正相关，这一结果表明NUF2可能通过抑制效应T细胞的肿瘤浸润，同时促进免疫抑制性巨噬细胞的极化，削弱抗肿瘤免疫应答[34]。Daiko 等针对 HLA-A*24:02 阳性食管癌患者的探索性临床试验表明，含 NUF2 肽段的 S-588410 疫苗可显著增加肿瘤微环境中功能性细胞毒性 T 淋巴细胞（CD8⁺Granzyme B⁺及 CD8⁺PD-1⁺细胞）的密度，并上调 PD-L1 的表达，证实 NUF2 作为癌睾抗原可诱导特异性免疫应答[21]。
NUF2 weakens anti-tumor immune responses by inhibiting the infiltration of anti-tumor immune cells. Studies indicate that high NUF2 expression is significantly associated with reduced infiltration of CD8+ T cells, dendritic cells (DCs), and natural killer cells (NK cells) in various gastrointestinal cancers. In esophageal squamous cell carcinoma, NUF2 expression levels show a significant positive correlation with tumor purity but a negative correlation with dendritic cell infiltration, suggesting that NUF2 may promote disease progression by suppressing the anti-tumor immune microenvironment [18]. Analysis of the TIMER database reveals that in gastric cancer, NUF2 transcript levels exhibit a significant negative correlation with high immune cell infiltration (macrophages, neutrophils, B cells, CD4+ T cells, CD8+ T cells, and dendritic cells), implying that NUF2 may inhibit anti-tumor immune responses [16, 26]. In liver cancer, NUF2 expression is significantly correlated with reduced CD8⁺ T cell and regulatory T cell infiltration, further supporting the notion that NUF2 may facilitate tumor progression by suppressing anti-tumor immunity [36]. Wang et al. further demonstrated that in hepatocellular carcinoma tissues, NUF2 mRNA levels negatively correlate with the infiltration density of CD8+ cytotoxic T lymphocytes (CTLs) but positively correlate with the proportion of M2-type tumor-associated macrophages (TAMs). This finding suggests that NUF2 may impair anti-tumor immune responses by inhibiting effector T cell infiltration while promoting the polarization of immunosuppressive macrophages [34]. Daiko et al.'s exploratory clinical trial involving HLA-A*24:02-positive esophageal cancer patients showed that the S-588410 vaccine containing NUF2 peptides significantly increased the density of functional cytotoxic T lymphocytes (CD8⁺Granzyme B⁺ and CD8⁺PD-1⁺ cells) in the tumor microenvironment and upregulated PD-L1 expression, confirming that NUF2, as a cancer-testis antigen, can induce specific immune responses [21].
NUF2通过调控糖酵解与氧化磷酸化平衡，塑造免疫抑制代谢微环境。在胆管癌中，NUF2通过抑制TFR1的自噬降解，促进p-p38和p-ERK的上调，激活MAPK通路，从而抑制自噬并促进ROS积累，进一步影响肿瘤免疫微环境[14]。
NUF2 shapes an immunosuppressive metabolic microenvironment by regulating the balance between glycolysis and oxidative phosphorylation. In cholangiocarcinoma, NUF2 inhibits autophagic degradation of TFR1, promotes upregulation of p-p38 and p-ERK, and activates the MAPK pathway, thereby suppressing autophagy and facilitating ROS accumulation, which further impacts the tumor immune microenvironment [14].
NUF2调控氧化应激
NUF2 regulates oxidative stress
活性氧（Reactive Oxygen Species, ROS）在癌症中具有双重调控作用，其表达水平的变化直接影响肿瘤的发生、发展和治疗。NUF2通过干扰线粒体代谢稳态及氧化还原平衡，系统性调控肿瘤微环境（TME）中的ROS水平，从而影响肿瘤进展及免疫逃逸。在肝癌中，GSVA富集分析则显示，NUF2在肝癌中主要参与甘氨酸、丝氨酸和苏氨酸代谢[34]。在肾透明细胞癌中，NUF2 mRNA 的高表达与丙酸代谢、丙酮酸代谢、柠檬酸盐循环 TCA 循环、丁酸代谢以及缬氨酸、亮氨酸和异亮氨酸降解等途径的下调有关 [58]。这些代谢途径的下调可促进活性氧（ROS）蓄积[59]。活性氧（ROS）的过量产生是氧化应激的重要指标[60]。在肝癌中，NUF2通过稳定ERBB3-PI3K/AKT轴抑制抗氧化系统、驱动糖酵解代谢增加ROS生成，促进氧化应激[8]。HBV相关肝癌的单细胞分析显示，NUF2高表达与线粒体代谢重编程密切相关：其通过抑制PGC-1α/FOXO1通路，削弱线粒体氧化磷酸化（OXPHOS），导致电子传递链功能障碍及ROS泄漏 [29]。在胆囊癌（GBC）中，NUF2通过PI3K/AKT通路促进ECM重塑，增加胶原沉积引发的基质刚度，进一步诱导NADPH氧化酶（NOX）依赖性ROS生成，形成促癌微环境[15]
Reactive Oxygen Species (ROS) play a dual regulatory role in cancer, and changes in their expression levels directly affect tumor initiation, progression, and treatment. NUF2 systematically regulates ROS levels in the tumor microenvironment (TME) by disrupting mitochondrial metabolic homeostasis and redox balance, thereby influencing tumor progression and immune evasion. In hepatocellular carcinoma (HCC), GSVA enrichment analysis revealed that NUF2 is primarily involved in glycine, serine, and threonine metabolism [34]. In clear cell renal cell carcinoma, high expression of NUF2 mRNA is associated with the downregulation of pathways such as propionate metabolism, pyruvate metabolism, the citrate (TCA) cycle, butyrate metabolism, and the degradation of valine, leucine, and isoleucine [58]. The downregulation of these metabolic pathways can promote the accumulation of ROS [59]. Excessive ROS production is a key indicator of oxidative stress [60]. In HCC, NUF2 suppresses the antioxidant system by stabilizing the ERBB3-PI3K/AKT axis, drives glycolytic metabolism to increase ROS generation, and promotes oxidative stress [8]. Single-cell analysis of HBV-related HCC showed that high NUF2 expression is closely linked to mitochondrial metabolic reprogramming: it weakens mitochondrial oxidative phosphorylation (OXPHOS) by inhibiting the PGC-1α/FOXO1 pathway, leading to electron transport chain dysfunction and ROS leakage [29]. In gallbladder cancer (GBC), NUF2 promotes extracellular matrix (ECM) remodeling via the PI3K/AKT pathway, increasing collagen deposition-induced matrix stiffness, which further induces NADPH oxidase (NOX)-dependent ROS generation, creating a pro-tumorigenic microenvironment [15].
靶向 NUF2治疗癌症的临床研究
Clinical Research on Targeting NUF2 for Cancer Treatment
以上研究表明NUF2通过多种途径参与消化道癌症的发生和发展，这说明NUF2很可能成为极具临床应用前景的新型抗癌靶点。近年来，针对NUF2的靶向治疗研究已从基础研究快速向临床转化推进。目前，全球范围内有多项以NUF2为治疗靶点的临床试验正在进行中。根据美国临床试验注册中心（https://clinicaltrials.gov/）, UMIN 临床试验注册中心(https://www.umin.ac.jp/ctr/index-j.htm)以及欧盟临床试验注册中心（https://www.clinicaltrialsregister.eu/）注册数据，截至目前，已有23项NUF2为靶点治疗癌症的临床试验（表2），其中8已取得可喜的结果（表3）。
The above studies demonstrate that NUF2 participates in the initiation and progression of gastrointestinal cancers through multiple pathways, suggesting that NUF2 is likely to become a promising novel anticancer target with significant clinical potential. In recent years, research on NUF2-targeted therapies has rapidly advanced from basic research toward clinical translation. Currently, multiple clinical trials targeting NUF2 are underway worldwide. According to data registered in the U.S. ClinicalTrials.gov (https://clinicaltrials.gov/), the UMIN Clinical Trials Registry (https://www.umin.ac.jp/ctr/index-j.htm), and the EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/), as of now, 23 clinical trials targeting NUF2 for cancer treatment have been registered (Table 2), with 8 already yielding encouraging results (Table 3).
NUF2为靶点治疗消化道癌症的临床试验有6项，其中5项已取得可喜结果。A：NCT04316689临床试验结果显示S-488210/S-488211 通常耐受性好，所有包括食管癌的实体瘤患者均至少出现 1 例不良事件（AE），最常见的为 1 级注射部位反应，有 2 例 3 级治疗相关不良事件（高血压和注射部位反应），但均未达到剂量限制毒性标准，没有治疗相关的严重不良事件，所有患者均引发了强烈的 CTL 反应，支持后续开展S-488210/S-488211 与 PD-L1 阻断剂联合使用的 2 期研究[61]。B：UMIN000023324临床试验结果显示12 名 （80%） 参与者发生了与治疗相关的不良事件 （AE）。注射部位反应是最常报告的 AE （1 级，n = 1;2 级，n = 11），与接种疫苗前相比，疫苗接种后肿瘤组织中 CD8 + 、 CD8 + 颗粒酶 B + 、 CD8 + 程序性死亡 1 阳性 （PD-1+） 和程序性死亡配体 1 阳性 （PD-L1+） 细胞的密度更高，所有食管癌患者都诱导了 5 种肽中的至少一种的 CTL 反应，S-588410 在食管癌中诱导肿瘤免疫反应 [21]。C：UMIN000016954临床试验结果显示S-588410安全性可接受，注射部位反应是 S-588410 组中最常见的治疗中出现的不良事件，S-588410 诱导免疫应答，在 12 周内接受 S-588410 治疗的食管鳞状细胞癌患者中观察到 132/134 （98.5%） 的 CTL 诱导，在接受 S-588410 治疗的上胸食管鳞状细胞癌、3 级注射部位反应或高 CTL 强度的患者中观察到生存期延长[62]。D：UMIN000003229临床试验结果显示多肽疫苗接种耐受性良好，接种疫苗后未观察到 3 级或 4 级不良事件。在所有晚期胆道癌患者中观察到肽特异性 T 细胞免疫反应，9 名患者中有 5 名患者病情稳定，中位 PFS 和 OS 分别为 3.4 个月和 9.7 个月，PD 判断后的 2 级注射部位反应和持续接种似乎对 OS 有预后 [39]。E: UMIN000004337临床试验结果显示多肽疫苗耐受性良好，接种后未观察到 3 级或 4 级不良事件，在所有 9 例晚期胰腺癌患者中检测到肽特异性 T 细胞反应，其中 4 例患者观察到临床益处，中位 PFS 和 OS 分别为 90 和 207 d，在接受基于肽的抗癌疫苗治疗的晚期胰腺癌患者中，引发多种强大的肽特异性 T 细胞反应以及宿主淋巴细胞的状态可能是有用的预后因素[44]。
There are 6 clinical trials targeting NUF2 for the treatment of gastrointestinal cancers, with 5 showing promising results.
A: The NCT04316689 clinical trial results indicated that S-488210/S-488211 was generally well-tolerated. All solid tumor patients, including those with esophageal cancer, experienced at least one adverse event (AE). The most common was grade 1 injection site reactions, with 2 cases of grade 3 treatment-related AEs (hypertension and injection site reaction), neither meeting the dose-limiting toxicity criteria. No treatment-related serious AEs occurred, and all patients exhibited strong CTL responses, supporting further phase 2 studies combining S-488210/S-488211 with PD-L1 blockade [61].
B: The UMIN000023324 clinical trial results showed that 12 (80%) participants experienced treatment-related AEs. Injection site reactions were the most frequently reported AEs (grade 1, n = 1; grade 2, n = 11). Compared to pre-vaccination, post-vaccination tumor tissues exhibited higher densities of CD8+, CD8+ granzyme B+, CD8+ PD-1+, and PD-L1+ cells. All esophageal cancer patients developed CTL responses to at least one of the 5 peptides, demonstrating that S-588410 induces tumor immune responses in esophageal cancer [21].
C: The UMIN000016954 clinical trial results confirmed the acceptable safety profile of S-588410, with injection site reactions being the most common treatment-emergent AE. S-588410 induced immune responses, with CTL induction observed in 132/134 (98.5%) esophageal squamous cell carcinoma patients treated within 12 weeks. Prolonged survival was noted in patients with upper thoracic esophageal squamous cell carcinoma, grade 3 injection site reactions, or high CTL intensity [62].
D: The UMIN000003229 clinical trial results demonstrated good tolerability of peptide vaccination, with no grade 3 or 4 AEs observed post-vaccination. Peptide-specific T-cell immune responses were detected in all advanced biliary tract cancer patients, with stable disease in 5 out of 9 patients. Median PFS and OS were 3.4 months and 9.7 months, respectively. Grade 2 injection site reactions and continued vaccination post-PD assessment appeared to have prognostic value for OS [39].
E: The UMIN000004337 clinical trial results indicated that the peptide vaccine was well-tolerated, with no grade 3 or 4 AEs observed. Peptide-specific T-cell responses were detected in all 9 advanced pancreatic cancer patients, with clinical benefit observed in 4. Median PFS and OS were 90 and 207 days, respectively. The induction of robust peptide-specific T-cell responses and host lymphocyte status may serve as useful prognostic factors in advanced pancreatic cancer patients treated with peptide-based anticancer vaccines [44].
尽管靶向NUF2的治疗策略，特别是基于多肽的癌症疫苗（如S-588410、S-488210/S-488211）已在多项临床试验中展现出诱导特异性细胞毒性T淋巴细胞（CTL）反应的潜力，但其临床转化仍面临显著挑战。多数研究为 Ⅰ/Ⅱ 期，聚焦安全性及免疫原性验证，缺乏大规模 Ⅲ 期数据；现有试验患者数多为 6-60 例，样本量小，难以排除个体差异对疗效的影响；疗效方面，仅部分患者达到疾病稳定，完全缓解或部分缓解罕见，提示单靶点疫苗可能难以彻底抑制肿瘤进展；现有疫苗依赖 HLA-A*2402 基因型，限制了非该基因型患者的获益；当前研究以单药疫苗为主，缺乏与化疗、靶向药或免疫检查点抑制剂的联合探索。（这段加不加）
Although NUF2-targeted therapeutic strategies, particularly peptide-based cancer vaccines (such as S-588410, S-488210/S-488211), have demonstrated the potential to induce specific cytotoxic T lymphocyte (CTL) responses in multiple clinical trials, their clinical translation still faces significant challenges. Most studies are Phase I/II, focusing on safety and immunogenicity validation, with a lack of large-scale Phase III data; existing trials typically involve only 6-60 patients, limiting the ability to account for individual variability in treatment efficacy; in terms of outcomes, only a subset of patients achieve disease stabilization, with complete or partial responses being rare, suggesting that single-target vaccines may be insufficient to fully suppress tumor progression; current vaccines rely on the HLA-A*2402 genotype, restricting benefits for patients without this genotype; existing research primarily explores monotherapy vaccines, lacking combination strategies with chemotherapy, targeted drugs, or immune checkpoint inhibitors.
展望
Prospects
综上所述，NUF2作为NDC80复合体的核心组分，在消化道癌症发生发展中发挥多重关键作用。现有研究证实，NUF2通过调控空细胞周期，细胞凋亡，细胞迁移与侵袭，氧化应激，免疫微环境重塑等多重分子机制，在消化道癌症进展中发挥核心调控作用。其表达水平与肿瘤恶性程度、临床分期及不良预后显著相关，具有重要的诊断和预后评估价值。基于这些发现，NUF2不仅可作为消化道癌症精准诊疗的新型生物标志物，更展现出成为新型抗癌靶点的巨大潜力。
In summary, as a core component of the NDC80 complex, NUF2 plays multiple critical roles in the development and progression of gastrointestinal cancers. Current research confirms that NUF2 exerts central regulatory functions in gastrointestinal cancer progression through diverse molecular mechanisms, including cell cycle regulation, apoptosis, cell migration and invasion, oxidative stress, and immune microenvironment remodeling. Its expression levels significantly correlate with tumor malignancy, clinical stage, and poor prognosis, highlighting its diagnostic and prognostic value. Based on these findings, NUF2 not only serves as a novel biomarker for precision diagnosis and treatment of gastrointestinal cancers but also exhibits substantial potential as a new anticancer target.
然而，目前NUF2相关研究仍处于起步阶段，仍存在一些局限于不足：如目前大部分研究仍停留在生物信息学预测与体外验证层面，缺乏系统的体内机制研究；部分研究样本量有限与研究对象具有局限性，影响结果的普适性；作用机制研究不够深入，NUF2在免疫调控和氧化应激中的作用机制相关研究较少。因此，未来的研究应聚焦于扩大样本量、优化药物配方、评估长期安全性，并深入探讨NUF2在不同消化道癌症中的具体作用机制，以推动这一领域的进一步发展。
However, current NUF2-related research remains in its early stages, with several limitations: most studies are still confined to bioinformatics predictions and in vitro validation, lacking systematic in vivo mechanistic investigations; some studies have limited sample sizes and restricted study populations, affecting the generalizability of results; mechanistic research remains insufficiently deep, with few studies exploring NUF2's roles in immune regulation and oxidative stress. Therefore, future research should focus on expanding sample sizes, optimizing drug formulations, evaluating long-term safety, and elucidating the specific mechanisms of NUF2 in different gastrointestinal cancers to advance this field further.
