作者: Zheng, Ningqian ; Liu, Yun ; Xu, Chen ; Ye, Zhiqian ; Zuo, You ; Xu, Guiqin ; Xu, Wangjie ; Zhang, Li ; Chen, Zehong ; Yang, Zhaojuan ; Liu, Yingbin ; Liu, Yongzhong ; Xiang, Lvzhu

Intrahepatic cholangiocarcinoma (iCCA) possesses the immunosuppressive tumor microenvironment (TME) that limits the effectiveness of immunotherapy. Genetic alterations of the coat protein complex Ⅰ (COPⅠ) lead to STING activation and inflammatory immune response. This study aims to address whether targeting COPⅠ can be exploited as a strategy to elicit immune response and inhibit iCCA progression. Here, we demonstrated that the COPⅠ subunits were highly expressed in human and mouse iCCA tissues. Genetic and pharmacological inhibition of COPⅠ suppressed growth of the mouse autochthonous iCCAs driven by activated oncogenes. Disruption of COPⅠ increased T cell presence in tumor environment and elicited anti-tumor T cell response through activating STING-type-I interferon (IFN-I) pathway. Neutralizing CD8⁺ T cell or STING deletion efficiently counteracted the suppression of iCCA growth by targeting COPⅠ. In addition, the Wnt/β-catenin signaling was dramatically attenuated in tumor cells by STING activation in the context of COPⅠ disruption. Notably, targeting COPⅠ markedly potentiates the therapeutic efficacy of anti-PD-1 in suppressing iCCA growth. In conclusion, our study reveals that targeting COPⅠ effectively suppresses tumor growth by enhancing T cell presence and function in mouse iCCA. STING activation by COPⅠ inhibition dedicates the T cell control of iCCA growth. COPⅠ is a potential target for iCCA treatment.

2025-06-02·JOURNAL OF CELL BIOLOGY

ZBTB17/MIZ1 promotes peroxisome biogenesis by transcriptional regulation of PEX13

Article

作者: Zhuang, Min ; Liu, Hongqin ; Chen, Xi ; Wang, Hanlin ; Zhuang, Guanglei ; Zhu, Zheng-Jiang

Peroxisomes are integral metabolic organelles involved in both catabolic and anabolic processes in humans, with defects linked to diseases. The functions of peroxisomes are regulated at transcriptional, translational, and posttranslational levels. In this study, we employed the CRISPR/Cas9-based screening of a ubiquitin ligase library to identify regulators of human peroxisomes. We discovered that ZBTB17 (MIZ1) plays a role in regulating the import of proteins into peroxisomes. Independent of its ubiquitin ligase activity, ZBTB17/MIZ1 operates as a transcription factor to modulate the expression of key importer PEX13, influencing the localization of peroxisomal enzymes. Furthermore, metabolomic profiling reveals that knockdown of ZBTB17 or PEX13 results in similar metabolic alterations, with downregulated purine synthesis. Collectively, we identify ZBTB17 as a key regulator of peroxisomal protein import, thereby affecting peroxisomal function and nucleotide metabolism. Our findings provide insights into the multifaceted regulation of peroxisomes in complex human cells and shed light on the molecular mechanisms underlying ZBTB17’s role as a transcriptional regulator.

2025-06-01·Molecular Therapy-Methods & Clinical Development

Anti-HIV-1 HSPC-based gene therapy with safety kill switch to defend against and attack HIV-1 infection

Article

作者: Brinkley, Alexander ; Chen, Grace ; Jakramonpreeya, Natnicha ; An, Dong Sung ; Zhang, Jian ; Guo, Qi ; Zhen, Anjie ; Parikh, Keval

Hematopoietic stem/progenitor cell (HSPC)-based anti-HIV-1 gene therapy holds promise to provide life-long remission following a single treatment. Here we report a multi-pronged anti-HIV-1 HSPC-based gene therapy designed to defend against and attack HIV-1 infection. We developed a lentiviral vector capable of co-expressing three anti-HIV-1 genes. Two are designed to prevent infection, including a short hairpin RNA (shRNA) (CCR5sh1005) to knock down HIV-1 co-receptor CCR5 and a membrane-anchored HIV-1 fusion inhibitor (C46). The third gene is a CD4-based chimeric antigen receptor (CAR) designed to attack HIV-1-infected cells. Our vector also includes a non-signaling truncated human epidermal growth factor receptor (huEGFRt) which acts as a negative selection-based safety kill switch against transduced cells. Anti-HIV-1 vector-transduced human CD34⁺ HSPC efficiently reconstituted multi-lineage human hematopoietic cells in humanized bone marrow/liver/thymus (huBLT) mice. HIV-1 viral load was significantly reduced (1-log fold reduction, p < 0.001) in transplanted huBLT mice. Anti-huEGFR monoclonal antibody cetuximab (CTX) administration significantly reduced huEGFRt⁺ vector-modified cells (>4-fold reduction, p < 0.01) in huBLT mice. These results demonstrate that our strategy is highly effective for HIV-1 inhibition, and that CTX-mediated negative selection can deplete anti-HIV-1 vector-modified cells in the event of unwanted adverse effects in huBLT mice.

项与上海市肿瘤研究所相关的新闻（医药）

2025-05-06

·ioncology

乳腺癌领域这些“中国之声”将在2025年ASCO大会亮相，敬请期待！

编者按：2025年美国临床肿瘤学会年会（ASCO）将于美国东部时间（GMT-5）5月30日至6月3日在芝加哥召开。本次会议聚焦肿瘤治疗前沿，将呈现化疗、内分泌治疗、免疫治疗、靶向治疗及精准医学的最新进展。肿瘤瞭望特别整理本届大会乳腺癌领域中国专家/学者即将展示的研究题目，供读者参考，如有缺漏和错误，欢迎留言指正。Rapid Oral Abstract SessionBreast Cancer—Metastatic美国东部时间：5月30日14:45 – 16:15北京时间：5月31日03:45 – 05:15地点：Hall D2HER2-ADC trastuzumab rezetecan (SHR-A1811) in HER2-positive breast cancer with brain metastases: Update results from REIN trial.HER2-ADC trastuzumab rezetecan（瑞康曲妥珠单抗，SHR-A1811）治疗伴脑转移的HER2阳性乳腺癌：REIN试验的最新结果报告时间：15:21–15:27讲者：闫敏（河南省肿瘤医院）摘要号：1017A phase II clinical study of adebrelimab and bevacizumab combined with cisplatin/carboplatin in triple-negative breast cancer patients with brain metastases.阿得贝利单抗联合贝伐珠单抗与顺铂/卡铂治疗三阴性乳腺癌脑转移患者的II期临床研究报告时间：15:27–15:33讲者：李婷（复旦大学附属肿瘤医院）摘要号：1018Sacituzumab tirumotecan (sac-TMT) as first-line treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): Initial results from the phase II OptiTROP-Breast05 study.II期OptiTROP-Breast05研究的初步结果：Sacituzumab tirumotecan（芦康沙妥珠单抗，sac-TMT）作为不可切除的局部晚期/转移性三阴性乳腺癌（a/mTNBC）的一线治疗报告时间：15:45–15:51讲者：殷咏梅（江苏省人民医院）摘要号：1019Central Nervous System Tumors美国东部时间：5月31日15:00-16:30北京时间：6月1日04:00- 05:30地点：S102Utidelone in combination with etoposide and bevacizumab in HER2-negative breast cancer patients with brain metastasis: A prospective, single-arm, phase II trial.优替德隆联合依托泊苷和贝伐珠单抗治疗HER2阴性乳腺癌脑转移患者：一项前瞻性、单臂、II期试验报告时间：15:00-15:06讲者：史业辉（天津医科大学肿瘤医院）摘要号： 2012Breast Cancer—Local/Regional/Adjuvant美国东部时间：6月1日08:00-09:30北京时间：6月1日21:00-22:30地点：Hall B1Dalpiciclib (Dalp) plus endocrine therapy (ET) as adjuvant treatment for HR+/HER2– early breast cancer (BC): The randomized, phase 3, DAWNA-A trial.随机、3期、DAWNA-A研究：Dalpiciclib（达尔西利，Dalp）联合内分泌治疗（ET）作为HR+/HER2-早期乳腺癌（BC）的辅助治疗报告时间：09:00-09:06讲者：邵志敏（复旦大学附属肿瘤医院）摘要号：515Oral Abstract SessionBreast Cancer—Local/Regional/Adjuvant美国东部时间：6月2日15:00-18:00北京时间：6月3日04:00-07:00地点：Hall B1De-escalated neoadjuvant taxane plus trastuzumab and pertuzumab with or without carboplatin in HER2-positive early breast cancer (neoCARHP): A multicentre, open-label, randomised, phase 3 trial.一项多中心、开放标签、随机III期试验（neoCARHP）：降阶梯新辅助紫杉烷联合曲妥珠单抗及帕妥珠单抗±卡铂治疗HER2阳性早期乳腺癌中的疗效报告时间：15:00- 15:12讲者：王坤（广东省人民医院）摘要号：LBA500Poster Session美国东部时间：6月2日09:00-12:00北京时间：6月2日22:00-6月3日01:00地点：Hall A - Posters and ExhibitsBreast Cancer—Local/Regional/AdjuvantThe difference of clinical and molecular characteristics between HR-positive/HER2-positive and HR-negative/HER2-positive early breast cancer: A secondary analysis of 11 clinical trials.11项临床试验的二次分析：HR阳性/HER2阳性和HR阴性/HER2阳性早期乳腺癌的临床和分子特征差异讲者：郑红梅（湖北省肿瘤医院）摘要号：533Dynamic changes in circulating tumor DNA among Taiwanese early breast cancer patients undergoing upfront surgery: Results from the VGH-TAYLOR study.VGH-TAYLOR研究结果：台湾接受前期手术的早期乳腺癌患者循环肿瘤DNA的动态变化讲者：Chi-Cheng Huang（台北荣民总医院）摘要号：558Preoperative axillary US and MRI in early-stage breast cancer: Potential to prevent unnecessary axillary surgery.早期乳腺癌术前腋窝超声和MRI：预防不必要腋窝手术的潜力讲者：Xin Wang（四川大学华西医院）摘要号：577Neoadjuvant penpulimab combined with taxanes and carboplatin in triple-negative breast cancer: A single-arm, open-label, multi-center phase II clinical study (neoTAPPL).派安普利单抗联合紫杉类和卡铂新辅助治疗三阴性乳腺癌：一项单臂、开放标签、多中心II期临床研究（neoTAPPL）讲者：Wenting Yan（陆军军医大学西南医院）摘要号：588Neoadjuvant low-dose carboplatin and docetaxel in combination with toripalimab for early or locally advanced triple-negative breast cancer (NeoTOP): A single-arm phase 2 trial.低剂量卡铂、多西他赛联合特瑞普利单抗新辅助治疗早期或局部晚期三阴性乳腺癌（NeoTOP）：一项单臂2期试验讲者：唐军（中山大学肿瘤防治中心）摘要号：589Efficacy and safety of neoadjuvant TQB2102 in women with locally advanced or early HER2-positive breast cancer: A randomized, open-label, multi-centre phase 2 trial.随机、开放标签、多中心、II期研究：TQB2102新辅助治疗局部晚期或早期HER2阳性乳腺癌女性患者的疗效和安全性讲者：李俊杰（复旦大学附属肿瘤医院）摘要号：591SHR-A1811 as neoadjuvant therapy for HR-positive, HER2-low breast cancer: A single-arm, phase II clinical study.SHR-A1811用于HR阳性、HER2低表达乳腺癌的新辅助治疗：一项单组、II期临床研究讲者：Jiujun Zhu（河南省肿瘤医院）摘要号：594Exploration of the new classification of hormone receptor-positive breast cancer: Based on the genomic landscape of 2111 early to mid-stage Asian patients.探索激素受体阳性乳腺癌的新分类：基于2111例早中期亚洲患者的基因组图谱讲者：Cuiyun Zhang（河南省肿瘤医院）摘要号：596Neoadjuvant cadonilimab (anti-PD-1/CTLA-4 bispecific antibody) plus chemotherapy in early or locally advanced triple-negative breast cancer: A single-arm phase II trial (CABIN study).新辅助cadonilimab（抗PD-1/CTLA-4双特异性抗体）联合化疗治疗早期或局部晚期三阴性乳腺癌：一项单臂II期试验（CABIN研究）讲者：Tao Wu（湘雅常德医院）摘要号：599Biomarkers of neoadjuvant dalpiciclib in patients with operable HER2-negative luminal B breast cancer in the DANCER trial.DANCER试验中可手术HER2阴性luminal B型乳腺癌患者新辅助达尔西利治疗的生物标志物研究讲者：Yunxiang Zhou（浙江大学医学院附属第二医院）摘要号：600Eliminating breast surgery for triple negative or HR-/HER2+ breast cancer patients with clinical complete response to combined neoadjuvant chemotherapy and neoadjuvant radiotherapy: A multicenter, phase 2 trial (EBCS).对新辅助化疗和新辅助放疗联合治疗后达到临床完全缓解的三阴性或HR-/HER2+乳腺癌患者免除乳房手术：一项多中心、2期试验（EBCS）讲者：杨正军（天津医科大学肿瘤医院）摘要号：TPS630Breast Cancer—MetastaticLongitudinal tissue analysis and correlation of microenvironmental changes with combined immunotherapy and targeted therapy response in metastatic breast cancer.纵向组织分析以及微环境变化与转移性乳腺癌联合免疫治疗和靶向治疗反应的相关性讲者：刘洁琼（中山大学孙逸仙纪念医院）摘要号：1022Phase I summary of the C406 (CART) efficacy and safety for an HER-2–positive breast cancer population.C406（CART）对HER2阳性乳腺癌人群治疗疗效和安全性的第一阶段总结讲者：Meili Sun（济南市中心医院）摘要号：1025A phase Ib/IIa study of BAT8010+BAT1006, an anti-HER2 monoclonal antibody-exatecan conjugate combined with an ADCC-enhanced HER2 mAb in patients with advanced solid tumors.BAT8010（HER2ADC）联合ADCC增强型BAT1006（HER2单抗）在晚期实体瘤患者中的临床Ib/IIa期研究结果讲者：王树森（中山大学肿瘤防治中心）摘要号：1027JSKN003, a biparatopic HER2-targeting ADC, in heavily pretreated HER2-positive breast cancer: A pooled analysis of early-phase studies.JSKN003是一种双表位靶向HER2的ADC，用于既往接受过大量治疗的HER2阳性乳腺癌：早期研究的汇总分析讲者：Yiqun Du（复旦大学附属肿瘤医院）摘要号：1028Eribulin plus pyrotinib In trastuzumab-resistant HER2-positive advanced breast cancer: A single-arm, multicenter phase II trial (EPIC trial).艾立布林联合吡咯替尼治疗曲妥珠单抗耐药的HER2阳性晚期乳腺癌：一项单臂、多中心II期试验（EPIC试验）讲者：宋振川（河北医科大学第四医院）摘要号：1031Efficacy and safety results of TQB2930, a HER2-targeted bispecific antibody combined with chemotherapy in patients with HER2-positive breast cancer (BC) previously treated with ≥2 line treatments: Results from a phase 1b/2 study.TQB2930（一种靶向HER2的双特异性抗体）联合化疗用于既往接受过≥2线治疗的HER2阳性乳腺癌（BC）患者的疗效和安全性结果：来自1b/2期研究的结果讲者：张清媛（哈尔滨医科大学肿瘤医院）摘要号：1033Recurrence risk prediction model in HER2-positive early breast cancer after HER2-targeted therapy.HER2阳性早期乳腺癌靶向治疗后复发风险预测模型讲者：Qingyao Shang（中国医学科学院肿瘤医院）摘要号：1035Comprehensive results of ESG401, a TROP2-targeting ADC: Updated phase 1 analysis in advanced solid tumors靶向TROP2的ADC的ESG401：晚期实体瘤的更新1期分析的综合结果讲者：马飞（中国医学科学院肿瘤医院）摘要号：1044Landscape analysis of proteins in the development of breast cancer brain metastasis.乳腺癌脑转移发展中蛋白质的全景分析讲者：Dongyan Xu（浙江大学医学院附属第二医院）摘要号：1050Impact of BMI on CDK4/6 inhibitors efficacy and safety in advanced breast cancer: Results from a propensity score matched study—CAMELIA.BMI对晚期乳腺癌患者CDK4/6抑制剂疗效和安全性的影响：来自倾向评分匹配研究CAMELIA的结果讲者：Tianyu Zeng（南京医科大学第一附属医院）摘要号：1058A phase I/IIa study to evaluate the tolerability, safety, pharmacokinetics and efficacy of eciruciclib (BPI-1178) alone in advanced solid tumors and in combination with endocrine therapy for advanced or recurrent HR+/HER2- breast cancer.一项I/IIa期研究，评估eciruciclib（BPI-1178）单独用于晚期实体瘤，以及联合内分泌治疗用于晚期或复发性HR+/HER2-乳腺癌的耐受性、安全性、药代动力学和疗效讲者：Yiqun Du（复旦大学附属肿瘤医院）摘要号：1064SIM0270 in combination with palbociclib in patients with ER+/ HER2- advanced breast cancer: The phase Ib study.SIM0270联合哌柏西利治疗ER+/ HER2-晚期乳腺癌：Ib期研究讲者：吴炅（复旦大学附属肿瘤医院）摘要号：1068Preliminary efficacy and safety of TQB2102 in patients with HER2 low-expressing recurrent/metastatic breast cancer: Results from a phase 1b study.TQB2102治疗HER2低表达复发/转移性乳腺癌患者的初步疗效和安全性：来自1b期研究的结果讲者：王树森（中山大学肿瘤防治中心）摘要号：1090Camrelizumab plus nab-paclitaxel and cisplatin as first-line treatment for metastatic triple-negative breast cancer: A prospective, single-arm, open-label phase II trial.卡瑞利珠单抗联合白蛋白结合型紫杉醇和顺铂作为转移性三阴性乳腺癌的一线治疗：一项前瞻性、单臂、开放标签2期试验讲者：王碧芸（复旦大学附属肿瘤医院）摘要号：1101Safety and efficacy of the anti-TROP2 antibody-drug conjugate (ADC) IBI130 in patients (pts) with advanced triple-negative breast cancer (TNBC) and other solid tumors: Results from the phase 1 study.靶向TROP的抗体-药物偶联物（ADC）IBI130治疗晚期三阴性乳腺癌（TNBC）和其他实体瘤患者的安全性和疗效：1期研究的结果讲者：Fan Wu（福建省肿瘤医院）摘要号：1102SHR-A1811 plus adebrelimab in unresectable or metastatic triple-negative breast cancer: Results from a phase 1b/2 expansion cohort.SHR-A1811联合阿得贝利单抗治疗不可切除或转移性三阴性乳腺癌：1b/2期扩展队列的结果讲者：Yan Liang（南京医科大学第一附属医院）摘要号：1103ETER901: A randomized, open-label, phase III trial of anlotinib in combination with anti-PD-L1 antibody benmelstobart (TQB2450) versus nab-paclitaxel in first-line treatment of recurrent or metastatic triple-negative breast cancer.ETER901：一项随机、开放标签、3期试验，比较安罗替尼联合抗PD-L1抗体贝莫苏拜单抗（TQB2450）与白蛋白结合型紫杉醇（nab-紫杉醇）在复发或转移性三阴性乳腺癌一线治疗中的疗效讲者：王佳玉（中国医学科学院肿瘤医院）摘要号：1104Efficacy and safety of RC48-ADC in triple-negative breast cancer subtypes: FUSCC-TNBC-umbrella trial results.RC48-ADC治疗三阴性乳腺癌亚型的疗效和安全性：FUSCC-TNBC伞型试验结果讲者：Yin Liu（复旦大学附属肿瘤医院）摘要号：1109Impact of HER2-ultralow heterogeneity and optimal threshold on trastuzumab deruxtecan (T-DXd) efficacy in metastatic breast cancer: A national multicenter cohort study (HEROIC).HER2超低异质性和最佳阈值对T-DXd治疗转移性乳腺癌疗效的影响：一项国家多中心队列研究（HEROIC）讲者：邹宇田（中山大学孙逸仙纪念医院）摘要号：1117Phase II study evaluating 68Ga-FAPI PET uptake heterogeneity as a predictor of T-DXd treatment response in HER2-positive breast cancer brain metastases.II期研究评估68Ga-FAPI PET摄取异质性作为HER2阳性乳腺癌脑转移患者T-DXd治疗反应的预测因子讲者：王碧芸（复旦大学附属肿瘤医院）摘要号：TPS1122SIMRISE: A randomized phase III trial evaluating SIM0270 in combination with everolimus versus treatment of physician’s choice in patients with ER+/HER2- advanced breast cancer, previously treated with CDK4/6 inhibitors.SIMRISE：一项随机III期试验，在既往接受过CDK4/6抑制剂治疗的ER+/HER2-晚期乳腺癌患者中，评估SIM0270联合依维莫司对比医师选择的治疗方案的疗效。讲者：吴炅（复旦大学附属肿瘤医院）摘要号：TPS1128（来源：《肿瘤瞭望》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

ASCO会议临床结果抗体药物偶联物临床2期

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100 项与上海市肿瘤研究所相关的转化医学

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