Journal of Experimental & Clinical Cancer Research最新文献

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Precision immune regulation in KRAS-mutated cancers: the final piece of the puzzle? kras突变癌症的精确免疫调节:最后一块拼图?
IF 11.4 1区 医学
Journal of Experimental & Clinical Cancer Research Pub Date : 2025-07-03 DOI: 10.1186/s13046-025-03444-1
Shenao Fu, Jiayao Ma, Changjing Cai, Jun Tan, Xiangying Deng, Hong Shen, Shan Zeng, Yihong Chen, Ying Han
{"title":"Precision immune regulation in KRAS-mutated cancers: the final piece of the puzzle?","authors":"Shenao Fu, Jiayao Ma, Changjing Cai, Jun Tan, Xiangying Deng, Hong Shen, Shan Zeng, Yihong Chen, Ying Han","doi":"10.1186/s13046-025-03444-1","DOIUrl":"10.1186/s13046-025-03444-1","url":null,"abstract":"<p><p>In recent years, the development of targeted therapies for tumors with KRAS mutations has progressed rapidly, rendering the notion of KRAS as \"undruggable\" outdated. However, targeted therapies for KRAS mutations still face numerous challenges, including resistance, efficacy concerns, toxicity issues, and hurdles in drug development. Exploring alternative treatment modalities is thus essential. Extensive research has demonstrated that KRAS mutations significantly influence the immune microenvironment, presenting both challenges and opportunities for immunotherapy. Interestingly, it has been observed that different KRAS mutations and co-mutation subtypes exhibit significant variations in their immunological microenvironments, which undoubtedly impact immunotherapy choices. Here, we review the history of KRAS-targeted therapy, highlighting existing challenges, and summarize changes in the immune microenvironment of KRAS-mutated cancers and their potential therapeutic targets. We compare differences in the immune microenvironment across various mutation types and co-mutation subtypes, and offer perspectives on future research directions.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"189"},"PeriodicalIF":11.4,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12225162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144561810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Correction: Cellular hierarchy framework based on single-cell/multi-patient sample sequencing reveals metabolic biomarker PYGL as a therapeutic target for HNSCC. 更正:基于单细胞/多患者样本测序的细胞层次结构框架显示代谢生物标志物PYGL是HNSCC的治疗靶点。
IF 11.4 1区 医学
Journal of Experimental & Clinical Cancer Research Pub Date : 2025-07-03 DOI: 10.1186/s13046-025-03448-x
Jiezhong Guan, Xi Xu, Guo Qiu, Chong He, Xiaoyue Lu, Kang Wang, Xinyu Liu, Yuanyuan Li, Zihang Ling, Xuan Tang, Yujie Liang, Xiaoan Tao, Bin Cheng, Bo Yang
{"title":"Correction: Cellular hierarchy framework based on single-cell/multi-patient sample sequencing reveals metabolic biomarker PYGL as a therapeutic target for HNSCC.","authors":"Jiezhong Guan, Xi Xu, Guo Qiu, Chong He, Xiaoyue Lu, Kang Wang, Xinyu Liu, Yuanyuan Li, Zihang Ling, Xuan Tang, Yujie Liang, Xiaoan Tao, Bin Cheng, Bo Yang","doi":"10.1186/s13046-025-03448-x","DOIUrl":"10.1186/s13046-025-03448-x","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"184"},"PeriodicalIF":11.4,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12225105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Extracellular vesicle-mediated transmission of circPDLIM5 promotes lymphatic metastasis in prostate cancer. 细胞外囊泡介导的circPDLIM5传播促进前列腺癌的淋巴转移。
IF 11.4 1区 医学
Journal of Experimental & Clinical Cancer Research Pub Date : 2025-07-03 DOI: 10.1186/s13046-025-03443-2
Tao He, Wen Tao, Jie Zhang, Tao-Lin Xia, Bin Xu, Liao-Yuan Li
{"title":"Extracellular vesicle-mediated transmission of circPDLIM5 promotes lymphatic metastasis in prostate cancer.","authors":"Tao He, Wen Tao, Jie Zhang, Tao-Lin Xia, Bin Xu, Liao-Yuan Li","doi":"10.1186/s13046-025-03443-2","DOIUrl":"10.1186/s13046-025-03443-2","url":null,"abstract":"<p><p>For patients with prostate cancer (PCa), pelvic lymph node (LN) metastasis remains a major poor prognostic factor associated with cancer-specific mortality. VEGF-C is a major lymphangiogenic ligand that plays a vital role in LN metastasis in PCa. However, in some PCa caseswith LN metastasis,VEGF-C is not upregulated, indicating that some VEGF-C-independent mechanisms are essential for lymphangiogenesis.Herein, we confirmed that extracellular vesicles (EVs) derived from PCa cells could promote LN metastasis in PCa independent of VEGF-C. We identified an EV circular RNA, circPDLIM5, that could promote lymphangiogenesis and lymphatic metastasis in both PCa cell lines and mouse models. Mechanistically, the packaging of circPDLIM5 into EVs was regulated by heterogeneous nuclear ribonucleoprotein A2B1. Subsequently, EVs were transmitted to human lymphatic endothelial cells, and EVs carrying circPDLIM5 could then directly interact with the transcription factor Yin Yang 1 to enhance the expression of Prospero homeobox 1, which is crucial for the formation, differentiation, and maturation of lymphatic vessels. Our findingshighlight the importance of a molecular mechanism mediated by EVs carrying circPDLIM5that is involved in lymphangiogenesis and LN metastasis in PCa; as a result, EVscarrying circPDLIM5 may be an attractive therapeutic target for LN-metastatic PCa.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"188"},"PeriodicalIF":11.4,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12224790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144561826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Inhibition of autophagy enhances the antitumor efficacy of T/CAR T cell against neuroblastoma. 抑制自噬可增强T/CAR - T细胞对神经母细胞瘤的抗肿瘤作用。
IF 12.8 1区 医学
Journal of Experimental & Clinical Cancer Research Pub Date : 2025-07-03 DOI: 10.1186/s13046-025-03453-0
Francesca De Mitri, Manuela Giansanti, Ombretta Melaiu, Dorothee Haas, Stefan Ebert, Nicola Tumino, Elisabetta Vulpis, Francesca Gatto, Beatrice Martuscelli, Manuela Antonioli, Elisabetta Sangiuliano, Simona Caruso, Marco Scarsella, Cristiano De Stefanis, Veronica Marabitti, Silvia Campello, Doriana Fruci, Paola Vacca, Ignazio Caruana, Francesca Nazio
{"title":"Inhibition of autophagy enhances the antitumor efficacy of T/CAR T cell against neuroblastoma.","authors":"Francesca De Mitri, Manuela Giansanti, Ombretta Melaiu, Dorothee Haas, Stefan Ebert, Nicola Tumino, Elisabetta Vulpis, Francesca Gatto, Beatrice Martuscelli, Manuela Antonioli, Elisabetta Sangiuliano, Simona Caruso, Marco Scarsella, Cristiano De Stefanis, Veronica Marabitti, Silvia Campello, Doriana Fruci, Paola Vacca, Ignazio Caruana, Francesca Nazio","doi":"10.1186/s13046-025-03453-0","DOIUrl":"10.1186/s13046-025-03453-0","url":null,"abstract":"<p><p>Neuroblastoma (NB) is the most common extracranial solid tumor in children characterized by poor immune infiltration and resistance to adaptive immunity, contributing to its limited response to immunotherapy. A key mechanism underlying immune evasion in cancer is autophagy, a cellular process that plays many roles in cancer by supporting tumor survival and regulating immune interactions. In this study, we investigate the impact of autophagy inhibition on NB tumor growth, immune modulation, and the efficacy of immunotherapy. Using both murine and human NB cell lines, we demonstrate that genetic and pharmacological inhibition of autophagy significantly reduces 3D spheroid growth and upregulates major histocompatibility complex class I (MHC-I) expression. In vivo studies further confirm that targeting autophagy suppresses tumor progression and promotes immune infiltration into the tumor. Notably, we observe a significant increase in CD8<sup>+</sup> T cell recruitment and activation, suggesting that autophagy inhibition reshapes the immune landscape of NB, rendering it more susceptible to immune-mediated clearance. Crucially, autophagy inhibition also sensitizes NB cells to T cell-mediated cytotoxicity and enhances the therapeutic efficacy of GD2.CAR T-cell therapy. In vitro co-culture assays reveal increased CAR T cell-mediated tumor killing upon autophagy blockade, while in vivo models show prolonged tumor control and improved survival in treated mice compared to CAR T-cell therapy alone. These findings highlight autophagy as a key regulator of immune evasion in NB and suggest that its inhibition could serve as a promising therapeutic strategy to enhance immune recognition and improve the efficacy of immunotherapy.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"185"},"PeriodicalIF":12.8,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12224479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144561827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Phosphorylation of KIAA1429 promotes oxaliplatin resistance through activating the FZD7-Wnt signaling in BRAFV600E-mutated colorectal cancer. 在brafv600e突变的结直肠癌中,KIAA1429的磷酸化通过激活FZD7-Wnt信号通路促进奥沙利铂耐药。
IF 11.4 1区 医学
Journal of Experimental & Clinical Cancer Research Pub Date : 2025-07-03 DOI: 10.1186/s13046-025-03449-w
Taixuan Wan, Minyi He, Zhanzhen Liu, Yihang Zhou, Yebohao Zhou, Wei Xiao, Hao Xie, Shuangling Luo, Haoqi Zheng, Liang Kang, Yunxing Shi, Liang Huang
{"title":"Phosphorylation of KIAA1429 promotes oxaliplatin resistance through activating the FZD7-Wnt signaling in BRAF<sup>V600E</sup>-mutated colorectal cancer.","authors":"Taixuan Wan, Minyi He, Zhanzhen Liu, Yihang Zhou, Yebohao Zhou, Wei Xiao, Hao Xie, Shuangling Luo, Haoqi Zheng, Liang Kang, Yunxing Shi, Liang Huang","doi":"10.1186/s13046-025-03449-w","DOIUrl":"10.1186/s13046-025-03449-w","url":null,"abstract":"<p><strong>Background: </strong>The current standard therapeutic approach for colorectal cancer (CRC) is surgical operation and oxaliplatin (OXA)-based neoadjuvant chemotherapy. However, the acquisition of oxaliplatin resistance leads to an unfavorable prognosis in CRC. Therefore, there is an urgent need to elucidate the underlying mechanisms of oxaliplatin resistance.</p><p><strong>Methods: </strong>RNA-sequencing (RNA-seq) analysis of OXA-resistant CRC cell line was used to identify the driver of OXA resistance. Function of KIAA1429 in OXA-resistance was validated by in vivo and in vitro experiments. The underlying mechanism was investigated by Immunoprecipitation-Mass Spectrometry (IP-MS), Co-Immunoprecipitation (Co-IP), Immunofluorescence (IF), RNA immunoprecipitation (RIP) and RNA-seq.</p><p><strong>Results: </strong>KIAA1429 is significantly upregulated in oxaliplatin-resistant cell lines. However, we found that the expression level of KIAA1429 is not associated with the efficacy of neoadjuvant chemotherapy in colorectal cancer, indicating that the function of KIAA1429 is not solely determined by its expression level. We discovered that KIAA1429 exhibits differential nuclear and cytoplasmic distribution in colorectal cancer samples and that high cytoplasmic expression of KIAA1429 is associated with poor response to chemotherapy. Further investigation revealed that the nuclear-cytoplasmic distribution of KIAA1429 is regulated by BRAF-mediated phosphorylation. In vitro and in vivo experiments indicated that BRAF-mediated phosphorylation of KIAA1429 promotes oxaliplatin resistance by facilitating its aggregation in the cytoplasm. Mechanistically, we found that cytoplasmic KIAA1429 promotes WNT pathway activation by binding and stabilizing FZD7, thereby further enhancing cancer stemness and oxaliplatin resistance.</p><p><strong>Conclusions: </strong>This study elucidates the unique role of KIAA1429 phosphorylation in regulating its nuclear localization and function, offering novel insights into the mechanisms underlying OXA-resistance in CRC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"187"},"PeriodicalIF":11.4,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12225155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144561809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The non-metabolic function of 6PGD coordinates CCNA2 and HMGA2 expression to drive colorectal cancer progression and drug response. 6PGD的非代谢功能协调CCNA2和HMGA2的表达,驱动结直肠癌的进展和药物反应。
IF 11.4 1区 医学
Journal of Experimental & Clinical Cancer Research Pub Date : 2025-07-03 DOI: 10.1186/s13046-025-03450-3
Mingming Sun, Qi Yan, Xinru Zhai, Xintong Dai, Chenxin Yang, Huifang Zhao, Sizhen Lai, Jiyan Wang, Lian Li, Zhen Li, Yanping Li, Taoyuan Wang, Tao He, Jun Xue, Zhenghu Jia, Chunze Zhang, Shuai Zhang, Changliang Shan
{"title":"The non-metabolic function of 6PGD coordinates CCNA2 and HMGA2 expression to drive colorectal cancer progression and drug response.","authors":"Mingming Sun, Qi Yan, Xinru Zhai, Xintong Dai, Chenxin Yang, Huifang Zhao, Sizhen Lai, Jiyan Wang, Lian Li, Zhen Li, Yanping Li, Taoyuan Wang, Tao He, Jun Xue, Zhenghu Jia, Chunze Zhang, Shuai Zhang, Changliang Shan","doi":"10.1186/s13046-025-03450-3","DOIUrl":"10.1186/s13046-025-03450-3","url":null,"abstract":"<p><p>Emerging evidence demonstrates that the metabolic and non-metabolic functions of metabolic enzymes play a key role in tumorigenesis and progression. 6-phosphogluconate dehydrogenase (6PGD) is a key metabolic enzyme in the pentose phosphate pathway (PPP), which displays aberrant expressions and functions in cancer. However, whether 6PGD serves non-metabolic functions in regulating cancer progression and drug response has not been reported. Here, we found that highly expressed 6PGD contributes to colorectal cancer (CRC) tumor growth and tumor metastasis. Mechanistically, 6PGD binds to ALKBH5 and inhibits its activity through the non-metabolic activity of 6PGD; this increases m<sup>6</sup>A modification levels and the stability of MDM2 mRNA and decreases the p53 protein stability, subsequently activating the expression of CCNA2 and HMGA2, which are responses to CRC tumor growth and tumor metastasis. Collectively, these findings reveal the multi-functionality of 6PGD in promoting CRC tumor growth, tumor metastasis, and drug responses through its non-metabolic activity.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"186"},"PeriodicalIF":11.4,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12224427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144561811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Multicenter study correlating molecular characteristics and clinical outcomes of cancer cases with patient-derived organoids. 多中心研究将癌症病例的分子特征和临床结果与患者来源的类器官相关。
IF 11.4 1区 医学
Journal of Experimental & Clinical Cancer Research Pub Date : 2025-07-02 DOI: 10.1186/s13046-025-03437-0
Paloma Navarro, Tatiana P Grazioso, Arantzazu Barquín, Maria Barba, Mónica Yagüe, Carlos Millán, Irene López, Elena Sevillano, Miguel Quiralte, Paloma Fernández, Diego Losada, Eduardo Caleiras, Julia Calzas, Beatriz Jiménez, Sergio Ruiz-Llorente, Juan Justo, Félix Guerrero, Vital Hevia, Raquel Martín, Francisco José Pérez-Rodriguez, Julia Tejerina, Mario Prieto, Paula Comune, Juan Francisco Rodriguez-Moreno, Jesús García-Donás
{"title":"Multicenter study correlating molecular characteristics and clinical outcomes of cancer cases with patient-derived organoids.","authors":"Paloma Navarro, Tatiana P Grazioso, Arantzazu Barquín, Maria Barba, Mónica Yagüe, Carlos Millán, Irene López, Elena Sevillano, Miguel Quiralte, Paloma Fernández, Diego Losada, Eduardo Caleiras, Julia Calzas, Beatriz Jiménez, Sergio Ruiz-Llorente, Juan Justo, Félix Guerrero, Vital Hevia, Raquel Martín, Francisco José Pérez-Rodriguez, Julia Tejerina, Mario Prieto, Paula Comune, Juan Francisco Rodriguez-Moreno, Jesús García-Donás","doi":"10.1186/s13046-025-03437-0","DOIUrl":"10.1186/s13046-025-03437-0","url":null,"abstract":"<p><strong>Background: </strong>3D-spatial interaction between cancer cells influences tumor behavior, making it essential to replicate tumor structures for predicting patient outcomes.</p><p><strong>Methods: </strong>We collected data from three multicenter prospective studies to evaluate the ability to establish Patient-Derived Organoids (PDOs) from different biological samples and timepoints, correlating their characteristics and drug sensitivity with clinical outcomes.</p><p><strong>Results: </strong>From 184 patients (17 tumor types), 249 samples were collected: 149 (59.8%) from tumor tissue, 61 (24.5%) from peritoneal fluids, 39 (15.7%) from peripheral blood. Success rates for PDO establishment were 39.5%, 34.4%, and 25.6%, respectively. PDOs reproduced pathological and immunohistochemical patterns of source tumors, with pathogenic variants confirmed in 84% (21/25). In a series of 13 baseline and sequential PDOs from 9 patients undergoing treatment, responses to therapy mirrored patient responses during therapy.</p><p><strong>Conclusions: </strong>PDOs preserve tumor features, reflect disease progression, and predict treatment responses, providing valuable models to complement molecular testing in precision medicine.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"182"},"PeriodicalIF":11.4,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144555593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Elucidating the role of N-myristoylation in the excessive membrane localization of PD-L1 in hypoxic cancers and developing a novel NMT1 inhibitor for combination with immune checkpoint blockade therapy. 阐明n -肉豆肉酰化在缺氧癌症中PD-L1过度膜定位中的作用,并开发一种新的NMT1抑制剂与免疫检查点阻断治疗联合使用。
IF 12.8 1区 医学
Journal of Experimental & Clinical Cancer Research Pub Date : 2025-07-02 DOI: 10.1186/s13046-025-03438-z
Haoming Zhao, Zhen Zhang, Chaojun Zhang, Hexin Ma, Qingqing Wan, Xinran Zhao, Xu Wang, Ming Yan, Haiyan Guo, Jianjun Zhang, Wantao Chen
{"title":"Elucidating the role of N-myristoylation in the excessive membrane localization of PD-L1 in hypoxic cancers and developing a novel NMT1 inhibitor for combination with immune checkpoint blockade therapy.","authors":"Haoming Zhao, Zhen Zhang, Chaojun Zhang, Hexin Ma, Qingqing Wan, Xinran Zhao, Xu Wang, Ming Yan, Haiyan Guo, Jianjun Zhang, Wantao Chen","doi":"10.1186/s13046-025-03438-z","DOIUrl":"10.1186/s13046-025-03438-z","url":null,"abstract":"<p><strong>Background: </strong>Most cancers, including head and neck squamous cell carcinoma (HNSCC), frequently exhibit an approximately 80% lack of response to immune checkpoint blockade (ICB) therapy, largely attributed to hypoxia-induced tumor immune suppression. Although hypoxia is known to upregulate PD-L1 expression, the key mechanisms by which it enhances PD-L1 membrane localization and high expression remain elusive.</p><p><strong>Methods: </strong>We investigated the molecular mechanisms by which hypoxia enhances PD-L1 membrane localization in HNSCC cells. Additionally, we tested the efficacy of combining an anti-PD-1 antibody with the NMT1 inhibitor PCLX-001 in HNSCC xenograft mice and conducted a retrospective clinical study to assess NMT1 as a prognostic biomarker.</p><p><strong>Results: </strong>Our study revealed that hypoxia-inducible factor-1α (HIF1α) upregulates N-myristoyltransferase 1 (NMT1), which mediates the myristoylation of calcineurin B homologous protein 1 (CHP1). Myristoylated CHP1 binds to PD-L1, facilitating its rapid translocation to the cell membrane and increasing PD-L1-mediated immune evasion. The NMT1 inhibitor low-dose PCLX-001 blocks CHP1 myristoylation, disrupting excessive PD-L1 membrane localization and attenuating cancer immune suppression. In HNSCC xenograft mice, administering an anti-PD-1 antibody combined with low-dose PCLX-001 via intratumoral injection significantly improved the treatment response rate and produced synergistic anticancer effects with no significant weight loss. Furthermore, our retrospective clinical study demonstrated that NMT1 protein levels can serve as an independent prognostic biomarker for HNSCC.</p><p><strong>Conclusion: </strong>These findings provide robust theoretical support for the translational application of combining NMT1 inhibitors and ICB therapy in cancers under hypoxic conditions. This study introduces a combined cancer therapy strategy named \"spatial blockade plus signaling inhibition of PD-L1.\"</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"181"},"PeriodicalIF":12.8,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12219335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144555591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Immune checkpoint inhibition perturbs neuro-immune homeostasis and impairs cognitive function. 免疫检查点抑制扰乱神经免疫稳态,损害认知功能。
IF 11.4 1区 医学
Journal of Experimental & Clinical Cancer Research Pub Date : 2025-07-02 DOI: 10.1186/s13046-025-03442-3
Onwodi V Ifejeokwu, An H Do, Sanad M El Khatib, Nhu N Ho, Angel Zavala, Shivashankar Othy, Munjal M Acharya
{"title":"Immune checkpoint inhibition perturbs neuro-immune homeostasis and impairs cognitive function.","authors":"Onwodi V Ifejeokwu, An H Do, Sanad M El Khatib, Nhu N Ho, Angel Zavala, Shivashankar Othy, Munjal M Acharya","doi":"10.1186/s13046-025-03442-3","DOIUrl":"10.1186/s13046-025-03442-3","url":null,"abstract":"<p><strong>Background: </strong>Blockade of Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and Programmed Cell Death Protein 1 (PD-1) significantly improves progression-free survival in patients with cancers, including melanoma. In addition to unleashing antitumor immunity, immune checkpoint inhibition (ICI) therapies disrupt immune regulatory networks critical for maintaining homeostasis in various tissues, including the central nervous system (CNS). Despite growing reports of cancer- and ICI-related cognitive impairments among survivors, our understanding of the pathophysiology of ICI-related neurodegenerative effects is limited.</p><p><strong>Methods: </strong>In this study, we used a murine model of melanoma, cognitive function tests, and neuroimmunological assays to investigate the cellular mechanisms and impact of combinatorial blockade of CTLA-4 and PD-1 on brain function. Syngeneic melanoma was induced in C57Bl6 mice via intradermal injection of D4M-3A.UV2 melanoma cells. After confirmation of tumor growth, cancer-bearing and non-cancer mice received combinatorial treatment of anti-CTLA-4 (1 mg per dose, twice per week) and anti-PD-1 (200 µg per dose, thrice per week) for three weeks. One month after completing ICI treatment, mice were evaluated for learning, memory, and memory consolidation cognitive function tasks. Neuroinflammation, synaptic and myelin integrity, and immune cell status in the brain were analyzed to examine neuro-immunological changes post-ICI treatment.</p><p><strong>Results: </strong>While tumor-related alterations in brain function were evident, combined ICI treatment specifically disrupted synaptic integrity and reduced myelin levels independent of neurogenesis and neuronal plasticity in both cancer-bearing and non-cancer mice brains. Combined ICI selectively impaired hippocampal-dependent cognitive function. This was associated with a two-fold increase in T cell numbers within the brain along with immune activation of myeloid cells, especially microglia. Furthermore, an experimental autoimmune encephalomyelitis model revealed that combination ICI predisposes the CNS to exacerbated autoimmunity, highlighting neuroinflammation-related, and tumor-independent, neurodegenerative sequelae of combination ICI.</p><p><strong>Conclusion: </strong>Our results demonstrate that combinatorial blockade of CTLA-4 and PD-1 destabilizes neuroimmune-regulatory networks and activates microglia, contributing to long-term neurodegeneration and cognitive impairments. Therefore, selectively limiting microglial activation could be a potential avenue to preserve CNS functions while maintaining the therapeutic benefits of rapidly evolving ICIs and their combinations.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"183"},"PeriodicalIF":11.4,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144555592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Targeting glutamine metabolism as a potential target for cancer treatment. 谷氨酰胺代谢作为癌症治疗的潜在靶点。
IF 11.4 1区 医学
Journal of Experimental & Clinical Cancer Research Pub Date : 2025-07-01 DOI: 10.1186/s13046-025-03430-7
Wenxuan Zou, Zitao Han, Zihan Wang, Qian Liu
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