Journal of Experimental & Clinical Cancer Research最新文献

{"title":"NOTCH3 regulates myofibroblastic CAF differentiation via the P62-ROS signaling axis to promote bladder cancer progression.","authors":"Ding Hu, Chengquan Shen, Changxue Liu, Fei Xie, Xinning Wang, Hexiang Wang, Yunqing Chen, Xinzhao Zhao, Ruize Qin, Cheng Li, Huaixi Ge, Jianhang Zhu, Zhengze Xi, Yonghua Wang","doi":"10.1186/s13046-026-03751-1","DOIUrl":"10.1186/s13046-026-03751-1","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAFs) are important contributors to malignant progression in bladder cancer (BLCA), yet the mechanisms by which they promote tumor progression remain incompletely understood. In this study, we integrated patient-derived CAFs with bulk and single-cell transcriptomics, spatial transcriptomics, and multi-cohort clinical datasets to systematically define the molecular mechanisms underlying CAF-driven BLCA progression. Integrated analyses of bulk RNA sequencing, single-cell transcriptomics, spatial transcriptomics, immunohistochemistry, and multiplex immunofluorescence of paraffin-embedded tissues, together with PCR, immunoblotting, and immunofluorescence in patient-derived normal fibroblasts and CAFs, consistently demonstrated marked enrichment of NOTCH3 in CAFs in bladder cancer. Silencing of NOTCH3 attenuated extracellular matrix deposition, contractile capacity, intracellular ROS accumulation, and the ability of CAFs to support tumor growth. Mechanistically, TGF-β induced NOTCH3 transcription through SMAD2 binding to the NOTCH3 promoter. In turn, NOTCH3 recruited HSPA8 to promote K48-linked ubiquitination and proteasomal degradation of P62, thereby suppressing the P62-NRF2 antioxidant pathway and sustaining intracellular ROS accumulation. Restoration of P62 expression or pharmacological scavenging of ROS effectively reversed NOTCH3-driven myofibroblastic differentiation and stromal support of tumor growth. In vivo, CAF-specific deletion of NOTCH3 significantly inhibited tumor growth, reduced collagen deposition, and attenuated stromal remodeling in both subcutaneous and orthotopic bladder cancer models. Collectively, these findings identify CAF-intrinsic NOTCH3 as important regulator of myofibroblastic differentiation through integration of upstream TGF-β signaling with redox and proteostatic control, highlighting stromal NOTCH3 as a potential therapeutic target to limit malignant progression in BLCA.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148195173","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}

{"title":"B7-H3 CAR T cells eradicate intrahepatic cholangiocarcinoma and induce durable response.","authors":"Shahrzad Arya, Marco Ventin, Giulia Cattaneo, Martina Nebbia, Seyed Amir Sanatkar, Cristina Martin, Jingyu Jia, Bangjin Kim, Cedric A Bailey, Nabeel M Bardeesy, David T Ting, Vikram Deshpande, Xinhui Wang, Sandra Ryeom, Soldano Ferrone, Cristina R Ferrone","doi":"10.1186/s13046-026-03723-5","DOIUrl":"10.1186/s13046-026-03723-5","url":null,"abstract":"<p><strong>Background: </strong>Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver tumor, with an increasing incidence over the past two decades. While surgery offers a curative option, most patients present with advanced disease, for which current therapeutic options are ineffective. B7-H3 is an immune checkpoint molecule that is overexpressed in ICC relative to normal tissue, making it an attractive therapeutic target. Utilizing in vitro and in vivo models, we investigated the efficacy of a B7-H3-targeted CAR T to treat ICC.</p><p><strong>Methods: </strong>B7-H3 CAR T cells were generated from peripheral blood mononuclear cells of normal donors, transduced with a retroviral vector encoding a second generation B7-H3 specific CAR construct, incorporating an inducible caspase9 (iCas9) suicide gene-based safety switch. The anti-tumor activity of iCas9.B7-H3 CAR T cells against ICC was tested in vitro using human ICC cell lines and patient-derived organotypic tumor spheroids (PDOTS) and in vivo using xenograft models of ICC.</p><p><strong>Results: </strong>Human ICC cell lines, resected ICC samples from patients, and ICC tissue microarrays demonstrate homogeneous expression of B7-H3. iCas9.B7-H3 CAR T cells demonstrated potent anti-tumor activity in vitro against multiple patient-derived ICC cell lines. A single systemic dose of iCas9.B7-H3 CAR T cells induced complete and sustained eradication of orthotopic ICC tumors in a preclinical mouse model, even after tumor re-challenge. Locoregional delivery of CAR T cells via splenic and intra-tumoral injection was equally effective as systemic therapy.</p><p><strong>Conclusions: </strong>These results provide a strong rationale for evaluating the iCas9.B7-H3 CAR T cell strategy in clinical trials for patients with advanced ICC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13255452/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148165182","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}

{"title":"Ferroptosis-based therapeutic strategy targeting iron metabolism and SLC7A11 overcomes oxaliplatin resistance in patient-derived pancreatic cancer organoids.","authors":"Jin Ho Choi, Kyung Min Lee, Minsik Oh, Janghyun Noh, Yooyeon Kim, Eunhye Hwang, In Rae Cho, Woo Hyun Paik, Ji Kon Ryu, Ja-Lok Ku, Sang Hyub Lee","doi":"10.1186/s13046-026-03745-z","DOIUrl":"10.1186/s13046-026-03745-z","url":null,"abstract":"<p><strong>Background: </strong>Oxaliplatin resistance remains a significant challenge in pancreatic cancer (PC) treatment. Ferroptosis, an iron-dependent form of cell death characterized by lipid peroxidation, has emerged as a promising therapeutic target for overcoming chemotherapy resistance. This study investigated whether ferroptosis induction could overcome oxaliplatin resistance in PC.</p><p><strong>Methods: </strong>We established 42 patient-derived pancreatic cancer organoids (PDPCOs) and performed comprehensive molecular profiling including whole-exome sequencing, RNA sequencing and drug response assays. Cell viability, lipid peroxidation, iron levels, mitochondrial function, and drug synergy were evaluated. Survival analysis and differential gene expression analyses were conducted according to the biomarker candidate.</p><p><strong>Results: </strong>Transcriptomic analysis revealed distinct ferroptosis-related alterations in OXA-resistant PDPCOs, including a negative enrichment of ferroptosis suppressor genes. The ferroptosis inducer artesunate (ART) synergistically enhanced anticancer effects of OXA in cell lines and PDPCOs. Mechanistic studies demonstrated that combination therapy induced ferroptotic cell death by promoting lipid peroxidation, intracellular iron accumulation, and mitochondrial dysfunction. Combination therapy remarkably inhibited tumor growth in PDPCO-derived xenograft models. ART/OXA treatment upregulated expressions of iron transport proteins transferrin receptor (TFRC) and divalent metal transporter 1 (DMT1), contributing to ferroptosis induction. Overexpression of solute carrier family 7 member 11 (SLC7A11) conferred dual resistance to OXA and ART by suppressing ferroptosis, whereas its knockdown or pharmacological inhibition with erastin sensitized resistant cells to combination therapy. Notably, triple combination of ART, OXA, and erastin effectively overcame resistance in dual-resistant PDPCOs.</p><p><strong>Conclusions: </strong>Ferroptosis-based therapeutic strategies can overcome oxaliplatin resistance in PC, supporting further investigation of SLC7A11 as a candidate biomarker for ferroptosis-based therapeutic responsiveness.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13435938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148102246","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}

{"title":"DCLK1 regulates stemness and IL-6/STAT3-dependent metastatic niche formation in chemoresistant ovarian cancer.","authors":"Samrita Dogra, Sugantha Priya Elayapillai, Cole Hladik, Ameera Hasan, Maitreyee Das, Laura F Mortan, Dongfeng Qu, Courtney W Houchen, Bethany N Hannafon","doi":"10.1186/s13046-026-03739-x","DOIUrl":"10.1186/s13046-026-03739-x","url":null,"abstract":"<p><strong>Background: </strong>Metastasis is the leading cause of cancer-related mortality. In ovarian cancer, dissemination within the peritoneal cavity is the primary driver of patient death, underscoring a critical need to define the molecular mechanisms that initiate metastatic seeding and remodel the peritoneal microenvironment. Stem-like tumor cell programs are increasingly recognized as central to metastatic competence, yet the regulators linking tumor stemness to microenvironmental reprogramming remain poorly defined. Doublecortin-like kinase 1 (DCLK1), a serine/threonine kinase associated with tumor stemness, has been implicated in cancer progression, but its role in ovarian cancer metastasis is not fully understood.</p><p><strong>Methods: </strong>We employed genetic loss-of-function approaches to investigate the role of DCLK1 in ovarian cancer metastasis using in vivo intraperitoneal dissemination models. Metastatic burden and overall survival were assessed following DCLK1 depletion. DCLK1 expression was analyzed across patient-derived ascites cultures established from primary and recurrent ovarian cancer patients and correlated with markers of metastasis-initiating cells. Functional assays were used to assess tumor cell adhesion, mesothelial clearance, stemness features and mesothelial-to-mesenchymal transition. Targeted transcriptomic and secretome analyses identified DCLK1-regulated cytokine programs. Paracrine signaling to mesothelial cells was evaluated using pharmacologic inhibition of IL-6 receptor and downstream JAK-STAT signaling.</p><p><strong>Results: </strong>Genetic loss of DCLK1 significantly reduced intraperitoneal metastatic burden and prolonged overall survival in vivo. DCLK1 expression correlated strongly with established markers of stem-like, metastasis-initiating tumor cells across the patient-derived ascites cultures. Mechanistically, DCLK1 promoted early metastatic colonization by enhancing tumor cell adhesion, mesothelial clearance, and mesothelial-to-mesenchymal transition. Transcriptomic and secretome profiling identified interleukin-6 (IL-6) as a key downstream effector of DCLK1, with DCLK1 depletion leading to a marked reduction in IL-6 expression and secretion. Tumor-derived IL-6 activated JAK-STAT signaling in mesothelial cells, promoting mesothelial migration and a permissive metastatic niche; these effects were reversed by pharmacologic blockade of IL-6 receptor signaling.</p><p><strong>Conclusions: </strong>These findings position DCLK1 as a central molecular mediator linking tumor-intrinsic stemness to microenvironmental reprogramming that primes the peritoneal niche for metastatic progression. Targeting DCLK1 or downstream IL-6/JAK-STAT signaling may therefore offer a rational strategy to disrupt metastatic dissemination in ovarian cancer.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13404908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148057786","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}

{"title":"Correction: The KLF16/MYC feedback loop is a therapeutic target in bladder cancer.","authors":"Lisi Zheng, Jingxuan Wang, Shan Han, Li Zhong, Zefu Liu, Bin Li, Ruhua Zhang, Liwen Zhou, Xianchong Zheng, Zhenhua Liu, Cuiling Zeng, Ruonan Li, Yezi Zou, Liqin Wang, Yuanzhong Wu, Tiebang Kang","doi":"10.1186/s13046-026-03744-0","DOIUrl":"10.1186/s13046-026-03744-0","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13214454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148036869","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}

{"title":"Vaccine-expanded plasmablast-like B cells are associated with response to dendritic cell therapy in metastatic melanoma.","authors":"Marcella Tazzari, Silvia Carloni, Jenny Bulgarelli, Sara Pignatta, Martine Bocchini, Claudia Piccinini, Davide Angeli, Michela Tebaldi, Irene Azzali, Maria Maddalena Tumedei, Filippo Piccinini, Francesca Tauceri, Francesco Limarzi, Fabio Nicolini, Maria Teresa Bochicchio, Milena Urbini, Giovanni Foschi, Nicola Romanini, Francesco de Rosa, Anna Maria Granato, Elena Pancisi, Massimiliano Petrini, Laura Ridolfi","doi":"10.1186/s13046-026-03731-5","DOIUrl":"10.1186/s13046-026-03731-5","url":null,"abstract":"<p><strong>Background: </strong>Dendritic Cell Vaccines (DCVax) can induce tumor-specific immune responses, yet their clinical activity remains limited and poorly understood. We sought to identify cellular and molecular features within the vaccine product that are associated with clinical response to monocyte-derived DC vaccines in metastatic melanoma.</p><p><strong>Methods: </strong>We performed a multi-omics analysis integrating multiparametric flow cytometry, single-cell RNA sequencing of DCVax products, transcriptomic profiling of CD14⁺ monocytes from apheresis, and in situ characterization of pre-treatment melanoma biopsies. Patients were stratified into Responders (Rs) or Non-Responders (NRs) based on best overall response and Delayed-Type Hypersensitivity (DTH) status.</p><p><strong>Results: </strong>An unanticipated population of CD19⁺ plasmablast-like B cells was identified within the final DCVax products. These B cells, phenotypically distinct from their circulating precursors, were significantly enriched in Rs and mirrored a B-cell-inflamed baseline state characterized by mature Tertiary Lymphoid Structures (mTLS) in pre-treatment tumor lesions. While mature LAMP3⁺ DCs appeared at comparable frequencies across outcomes, LAMP3⁺ DCs from Rs selectively upregulated HSPA1A/B, consistent with enhanced antigen-processing programs. Transcriptomic signatures of antibody production in vaccine-resident B cells, together with Fc receptor expression on DCs, support a model in which B-cell activity may contribute to antigen loading and DC functional tuning during vaccine manufacturing, a hypothesis that warrants functional validation.</p><p><strong>Conclusions: </strong>Our findings reveal a previously unrecognized B-cell component of DCVax biology, suggesting that cooperative DC-B-cell interactions, combined with baseline B-cell/mTLS features, may contribute to shaping vaccine immunogenicity. While causality cannot be established from the present data, these insights offer actionable avenues for enhancing both vaccine manufacturing and patient selection, extending beyond melanoma.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13277274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148007323","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}

{"title":"Extracellular vesicles from chemotherapy-induced senescent tumor cells reprogram hepatic phospholipid metabolism to promote pancreatic cancer liver metastasis.","authors":"Bai'an Tao, Yecheng Xu, Wenteng Miao, Zhenmei Chen, Jichun Gu, Yujie Guo, Linjie Chen, Yang Di, Hang He, Chen Jin, Ji Li, Deliang Fu","doi":"10.1186/s13046-026-03741-3","DOIUrl":"10.1186/s13046-026-03741-3","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease, with over one-third of patients developing liver metastasis following neoadjuvant chemotherapy (NAC). This study aimed to investigate how the effect of chemotherapy on the primary tumor shapes the hepatic pre-metastatic niches (PMNs), which remains poorly understood.</p><p><strong>Methods: </strong>RNA sequencing was performed in a PDAC cohort to identify transcriptomic features associated with metastasis. We employed orthotopic and liver metastatic tumor models in mice to investigate the effects of extracellular vesicles derived from chemotherapy-treated PDAC cells, referred to as senescence-associated extracellular vesicles (S-EVs), on the hepatic PMNs. Mechanistically, we integrated proteomics and metabolomics to elucidate the molecular mechanisms by which S-EVs mediate hepatic metabolic reprogramming. Further, we utilized hepatocyte-specific Ache-knockout mice to validate the molecular mechanisms through which S-EVs promote liver metastasis in vivo.</p><p><strong>Results: </strong>Chemotherapy-induced senescence in primary tumors correlated with PDAC liver metastasis and poor prognosis. S-EVs facilitated PMNs formation by promoting hepatic phosphatidylcholine (PC) accumulation. Mechanistically, S-EV-delivered hnRNPA1 stabilized AChE mRNA, thereby driving PC accumulation in the liver. In vitro co-culture system, PC depletion in hepatocytes successfully restored the impaired cytotoxicity of CD8⁺ T cells caused by S-EVs. Consistently, hepatocyte-specific Ache ablation in vivo restored S-EV-impaired CD8⁺ T cells cytotoxicity. Inhibition of AChE with pyridostigmine remodeled the hepatic PMNs and suppressed liver metastasis.</p><p><strong>Conclusions: </strong>S-EVs from chemotherapy-induced senescent PDAC cells reshaped hepatic PMNs through AChE-dependent PC accumulation, thereby impairing CD8⁺ T cell cytotoxicity and promoting PDAC liver metastasis. Targeting AChE with pyridostigmine represented a promising strategy to prevent metastasis and augment the therapeutic efficacy of NAC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13374290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148007254","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}

{"title":"Epitranscriptomic silencing of the ZC3H13/m⁶A axis orchestrates immunosuppressive microenvironment remodeling in renal cell carcinoma via CSF2-mediated MDSCs recruitment.","authors":"Jinxiu Zheng, Xueting Zhao, Qing Men, Mengyi Zhou, Yuxin Che, Shenglu Liu, Likun Zan, Lingzhi Guo, Ying Shao, Shuhua Gao, Yanjie Ma, Xiaofeng Liu, Lijun Yang, Tao Yang","doi":"10.1186/s13046-026-03742-2","DOIUrl":"10.1186/s13046-026-03742-2","url":null,"abstract":"<p><strong>Background: </strong>The immunosuppressive tumor microenvironment (TME) is a cardinal driver of immune escape and resistance to immunotherapy in renal cell carcinoma (RCC). The N6-methyladenosine (m⁶A), the most prevalent RNA modification, critically governs tumor aggressiveness and TME reprogramming. We aimed to exploit whether and how tumor-intrinsic m⁶A modification driven by ZC3H13 (zinc finger CCCH-type containing 13) can dictate the immune landscape of RCC.</p><p><strong>Methods: </strong>Loss- and gain-of-function studies were performed in vitro and in allograft tumor model. Tumor-infiltrating immune cells were profiled with flow cytometry and immunostaining. The pivotal cytokine mediated by ZC3H13 depletion was identified through an integrated analysis of RNA-seq and PCR array. The molecular target of ZC3H13 was elucidated through integrated m⁶A sequencing and RNA sequencing.</p><p><strong>Results: </strong>Low ZC3H13 expression was an independent predictor of poor prognosis in RCC. Functionally, ZC3H13 silencing enhanced the malignant behaviors of RCC cells and drove an immunosuppressive microenvironment characterized by aberrant recruitment of myeloid-derived suppressor cells (MDSCs). Mechanistically, ZC3H13 promoted m⁶A methylation on UNC5CL (UNC-5 Family C-Terminal Like) mRNA, facilitating YTHDC1-mediated stabilization of UNC5CL transcripts, which subsequently suppressed the NF-κB-CSF2 signaling axis, ultimately inhibiting MDSCs accumulation. Furthermore, therapeutic targeting CSF2 in combination with anti-PD1 exerts stronger antitumor effects in RCC by synergistically reversing the MDSCs mediated immunosuppressive microenvironment.</p><p><strong>Conclusion: </strong>We identified that ZC3H13 loss unleashes the NF-κB-CSF2 signaling cascade via m⁶A-dependent silencing of UNC5CL, converting the RCC milieu into an MDSCs-dominated immunosuppressive niche. Targeting CSF2 combined with anti-PD1 may represent a novel therapeutic strategy to achieve better efficacy in RCC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13255311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147983976","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}

{"title":"Dual CAR-NK cells targeting PD-L1 and ErbB2 (HER2) exhibit cooperative CAR signaling and counteract solid tumor heterogeneity.","authors":"Kristin Freudenberg-Jahn, Idan Ben-Horin, Nivedha Murali Shankar, Maria Schuldt, Paola Ortiz-Montero, Liliana R Loureiro, Wiebke Rackwitz, Corinna Opitz, Lydia Krutz, Thomas Breither, Pranav Oberoi, Aline Häcker, Dirk Jäger, Jan Dominik Kuhlmann, Pauline Wimberger, Stephan R Künzel, Kristina Hölig, Anja Feldmann, Michael Bachmann, Winfried S Wels, Torsten Tonn, Jiri Eitler","doi":"10.1186/s13046-026-03722-6","DOIUrl":"10.1186/s13046-026-03722-6","url":null,"abstract":"<p><strong>Background: </strong>Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells have shown potent efficacy against hematologic malignancies. In contrast, solid tumors remain difficult to treat due to heterogeneous antigen expression and an immunosuppressive tumor microenvironment that fosters immune evasion and is driven to a large part by checkpoint-mediated inhibition.</p><p><strong>Methods: </strong>To overcome these barriers, we engineered novel dual CAR-NK cells targeting the immune checkpoint PD-L1 and the tumor-associated antigen ErbB2 (HER2). The clinically applicable NK-92 cell line was lentivirally transduced with PD-L1.CAR and ErbB2.CAR constructs. Antitumor activity was assessed across diverse solid tumor models using a comprehensive panel of in vitro and in vivo assays.</p><p><strong>Results: </strong>Dual CAR-NK cells exhibited potent and selective cytotoxicity against breast, pancreatic, gastric, and lung cancer cell lines expressing either one or both targets. Comparable efficacy was observed in 3D spheroid cultures and against patient-derived primary ovarian cancer cells. Notably, dual CAR-NK cells retained strong cytotoxicity when one antigen was absent or blocked, modeling immune escape through antigen loss - a feature absent in single CAR-NK cells. Mechanistically, each CAR independently activated the MEK/ERK pathway in an antigen-dependent manner, while dual CAR stimulation potentiated the signaling response in a cooperative manner. Furthermore, IFN-γ produced by NK cells upon encounter of resistant cancer cells was sufficient to induce PD-L1 upregulation, thereby enhancing the potency of the dual CAR system. In a PD-L1/ErbB2 double-positive breast cancer xenograft model, dual CAR-NK cells consistently outperformed single-target controls.</p><p><strong>Conclusions: </strong>Dual targeting of PD-L1 and ErbB2 enhances CAR-NK cell efficacy against refractory solid tumors by providing resilience to antigen heterogeneity and amplifying antitumor signaling through cooperative activation. This approach represents a promising and adaptable platform for clinical translation in solid tumor immunotherapy.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13198055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147976656","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}

{"title":"Targeting immunoglobulin superfamily member 9 (IGSF9) to overcome acute myeloid leukemia resistance to CAR-T therapy.","authors":"Xianhui Meng, Fangmin Li, Hong Yu, Chunling Li, Yuxiao Sun, Hongying Wang, Guantong Liu, Jiashen Zhang, Lijun Hui, Fang Li, Shuping Wei, Yaopeng Wang, Zunling Li","doi":"10.1186/s13046-026-03740-4","DOIUrl":"10.1186/s13046-026-03740-4","url":null,"abstract":"<p><strong>Background: </strong>CAR-T cell therapy faces substantial barriers in AML, yet the mechanisms by which AML evades CAR-T cell cytotoxicity-through tumor-intrinsic factors and microenvironmental suppression-remain poorly defined. IGSF9 has recently been identified as an immunosuppressive molecule selectively expressed on AML blasts, but its role in mediating resistance to CAR-T therapy is unknown.</p><p><strong>Methods: </strong>We examined IGSF9 expression in AML cells upon CAR-T challenge and conducted in vitro and in vivo assays to define its functional impact on CAR-T cell activity. To overcome IGSF9-mediated suppression, we evaluated two therapeutic strategies: antibody-mediated IGSF9 blockade and the generation of IGSF9-specific CAR-T cells (IG9BBz).</p><p><strong>Results: </strong>CAR-T-induced cytotoxic pressure upregulated IGSF9 on AML cells. IGSF9-positive AML cells exhibited resistance to CAR-T killing and impaired CAR-T persistence both in vitro and in vivo. Antibody blockade of IGSF9 restored CAR-T function in xenograft models. Moreover, IG9BBz CAR-T cells demonstrated potent and selective elimination of IGSF9-positive AML cells in both settings.</p><p><strong>Conclusions: </strong>Our findings identify a cytokine-driven IGSF9 resistance circuit that suppresses CAR-T cell function in AML. Therapeutic disruption of this pathway through IGSF9 blockade or IGSF9-specific CAR-T cells restores antitumor immunity and provides complementary strategies to overcome CAR-T resistance in AML.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13352843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147976611","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}