Experimental Hematology & Oncology最新文献

{"title":"Safety, efficacy, and pharmacokinetics of eratrectinib (VC004) in solid tumors with NTRK fusions: phase 1 results from a phase 1/2 study.","authors":"Shengyu Zhou, Changgong Zhang, Guowen Wang, Jun Qian, Gang Huang, Jiaqiang Wang, Suxia Luo, Youhua Zhu, Qingyuan Zhang, Ting Wei, Yongsheng Li, Zhendong Li, Dongyuan Zhu, Huarong Zhao, Meiyu Fang, Shoubing Zhou, Qing Xu, Yu Chen, Kejun Nan, Jiuwei Cui, Xueqiang Zhu, Yanchun Gong, Yong Wu, Xiaojuan Lai, Yuankai Shi","doi":"10.1186/s40164-026-00799-9","DOIUrl":"10.1186/s40164-026-00799-9","url":null,"abstract":"<p><strong>Background: </strong>Tropomyosin receptor kinases (TRK) tyrosine kinase inhibitors (TKIs) have demonstrated marked efficacy in neurotrophic receptor tyrosine kinase (NTRK) fusion positive tumors. However, resistance inevitably develops. Eratrectinib (VC004) is a next-generation selective TRK TKI which can overcome drug resistance.</p><p><strong>Methods: </strong>In this phase 1 study, patients with locally advanced or metastatic solid tumors were enrolled in the dose-escalation part. A standard 3 + 3 design was adopted to sequentially assign patients at 25 mg twice daily (BID), 50 mg BID, 100 mg BID, and 200 mg BID dose levels of oral eratrectinib. After each dose had been established, we expanded specific dose cohorts in patients with NTRK fusion positive locally advanced or metastatic solid tumors to obtain adequate data for safety, pharmacokinetics (PK), and efficacy. The primary endpoints of this study were safety, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D).</p><p><strong>Results: </strong>Between December 4, 2020 and November 4, 2021, 16 patients were enrolled in the dose-escalation part and a dose of 100 mg BID was identified as MTD. Between May 8, 2021 and March 19, 2025, 75 patients were enrolled in the dose-expansion part at doses of eratrectinib 25 mg BID, 50 mg BID, and 75 mg BID. Treatment-emergent adverse events (TEAEs) occurred in 94.7% (71/75) of patients. The most common treatment-related adverse events (TRAEs) included dizziness (51/75, 68.0%), anaemia (28/75, 37.3%), weight increased (27/75, 36.0%), hypertriglyceridemia (25/75, 33.3%). ≥ grade 3 TRAEs occurred in 17.3% (13/75) of patients. No TRAEs led to death. The dose of 50 mg BID was chosen as RP2D based on the results of safety, PK, and efficacy. At the RP2D dose, objective response rate (ORR) was 70% (21/30, 95% confidence interval 50.6-85.3).</p><p><strong>Conlusions: </strong>Eratrectinib demonstrated manageable safety profile and promising efficacy in patients with NTRK fusion positive solid tumors, representing a new treatment option for this patient population. Further studies to confirm the efficacy and safety of eratrectinib are ongoing. Trial registration NCT04614740 (ClinicalTrials.gov).</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":" ","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13591854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148327804","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":"MAGEC2 promotes tumorigenesis in multiple myeloma through USP16-mediated deubiquitination and stabilization of c-Myc.","authors":"Zihao Liu, Tingting Hu, Jie Min, Chen Wang, Yuhao Cao, Mengjie Guo, Jinjun Qian, Chunyan Gu, Ye Yang","doi":"10.1186/s40164-026-00782-4","DOIUrl":"10.1186/s40164-026-00782-4","url":null,"abstract":"<p><p>Multiple myeloma (MM) is an incurable malignancy characterized by clonal plasma cell proliferation, in which dysregulated ubiquitination plays a key pathogenic role. Using bufalin as a molecular probe, we identified melanoma-associated antigen C2 (MAGEC2) as a direct binding target and investigated its unconventional function beyond canonical E3 ligase modulation. MAGEC2 expression and clinical relevance were analyzed in patient cohorts. Functional assays (MTT, Western blot, CCK-8, flow cytometry) and mechanistic studies (co-immunoprecipitation, mass spectrometry, ubiquitination assays) were performed in vitro and in an adoptive B-cell transfer mouse model. High MAGEC2 expression was significantly associated with poor overall survival in MM patients. Functionally, MAGEC2 promoted malignant proliferation and induced resistance to adriamycin and bortezomib. Mechanistically, in addition to its known role in enhancing E3 ligase activity, MAGEC2 directly bound and increased the deubiquitinase activity of USP16, leading to c-Myc stabilization via reduced ubiquitination. Interactions among MAGEC2, USP16, and c-Myc were confirmed both in vitro and in vivo, establishing a MAGEC2-USP16-c-Myc axis. MAGEC2 overexpression also exacerbated bone lesions in vivo. Collectively, these findings identify MAGEC2 as both a prognostic biomarker and a promising therapeutic target in MM, and highlight its role as a multifunctional regulator of the ubiquitin system.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13292446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148316392","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":"Biology-informed risk stratification of glioblastoma by integrating MRI-based intratumoral heterogeneity with clinical features: a multicenter validation study.","authors":"Junfeng Zhang, Hong Guo, Xiaoxiao Ma, Yujue Zhong, Xiaojun Yu, Xiangbing Bian, Jianxing Hu, Caohui Duan, Yilong Huang, Jialing Wu, Mingliang Yang, Jian Hu, Xiaobo Zhang, Luhua Zhang, Rui Jiang, Xin Lou","doi":"10.1186/s40164-026-00788-y","DOIUrl":"10.1186/s40164-026-00788-y","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Refined risk stratification before randomization is clinically important for reducing prognostic imbalance across study arms when evaluating novel therapies for glioblastoma. However, current artificial intelligence-assisted prognostic models are often limited by complex computational pipelines, limited bedside applicability, and insufficient biological interpretability. This study aimed to develop a prognostic model, supported by an online-accessible platform, for individualized risk stratification of glioblastoma using MRI-based intratumoral heterogeneity and routinely available clinical features, and to investigate the biological meaning of model-driven risk stratification.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This retrospective multicenter study included 836 patients with isocitrate dehydrogenase-wildtype glioblastoma from six centers between October 1996 and May 2025. The habitat risk score (HRS) for each patient was derived from a proposed intratumoral heterogeneity index and quantitative metrics extracted from three-dimensional preoperative MRI-based vascular habitat mappings. Independent predictors of overall survival (OS) were identified using Cox proportional hazards regression analysis, and three prognostic models (HRS model, clinical model, and radio-clinical model) were developed and validated in spatial and temporal external sets. Model interpretability was assessed using time-stratified Shapley additive explanations (SHAP) analysis. A web-based interactive platform was implemented for rapid individualized risk assessment. The biological meaning of model-driven risk stratification was explored using transcriptomic and histologic profiling.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;HRS, Karnofsky performance status (KPS), O&lt;sup&gt;6&lt;/sup&gt;-methylguanine-DNA methyltransferase promoter methylation status, and extent of resection were identified as independent predictors of OS, with KPS and HRS contributing most strongly to survival prediction in SHAP analysis. The radio-clinical model demonstrated good predictive performance and outperformed the clinical model and the HRS model, with C-indexes of 0.74 and 0.77 in the spatial and temporal validation sets, respectively. It also effectively stratified patients into low- and high-risk groups regardless of first-line therapeutic regimen (log-rank, P &lt; 0.05). Mechanistically, high-risk tumors showed increased tumor stemness and expanded HIF1α-positive regions, whereas low-risk tumors exhibited an immune-stimulatory phenotype. The deployed web-based platform enabled rapid patient-specific risk estimation to support bedside application.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;This study establishes an interpretable and clinically deployable framework for glioblastoma risk stratification by integrating imaging-derived intratumoral heterogeneity with routine clinical features, without requiring complex computational infrastructure. The model also provides biologically grounded insights ","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":" ","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13560186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148294056","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":"Real-world evidence on infection risk in multiple myeloma treated with BiTEs and CAR-T cells: a meta-analysis.","authors":"Federico Spataro, Vanessa Desantis, Giuseppe Dicuonzo, Stefano Molica, Hermann Einsele, Angelo Vacca, Roberto Ria, Antonio Giovanni Solimando","doi":"10.1186/s40164-026-00798-w","DOIUrl":"10.1186/s40164-026-00798-w","url":null,"abstract":"<p><strong>Background: </strong>T-cell-redirecting therapies, including bispecific T-cell engagers (BiTEs) and chimeric antigen receptor T-cell (CAR-T) therapies, have substantially improved outcomes in relapsed or refractory multiple myeloma (RRMM). However, infectious complications remain a major safety concern, particularly in real-world settings, where patients are more heterogeneous than those enrolled in clinical trials.</p><p><strong>Methods: </strong>We conducted a systematic review and meta-analysis of real-world retrospective studies evaluating severe (grade 3-4) infections in adult patients with RRMM treated with approved BiTEs or CAR-T cell therapies. Pooled event rates were estimated using random-effects models. Heterogeneity was explored through subgroup analyses, meta-regression, and sensitivity analyses.</p><p><strong>Results: </strong>Sixteen studies encompassing 2,097 patients were included. Overall, 24.2% of patients developed grade 3-4 infections (pooled event rate 0.24; 95% CI, 0.21-0.28). Among BiTEs-treated patients (n = 1,602), the pooled severe infection rate was 0.26 (95% CI, 0.23-0.30), with higher rates observed for BCMA-directed BiTEs (0.27) compared with GPRC5D-directed BiTEs (0.25). CAR-T cell therapies (n = 495) were associated with a lower pooled infection rate (0.19; 95% CI, 0.12-0.27).</p><p><strong>Conclusions: </strong>In real-world practice, severe infections affect approximately one in four patients receiving T-cell-redirecting therapies for RRMM. Observed differences in infection rates across platforms and targets should be interpreted with caution, as they derive from indirect comparisons in non-randomized, heterogeneous cohorts. Nevertheless, these data support incorporating patient frailty and prior infection history into therapeutic decision-making. CAR-T therapy, or GPRC5D-directed BiTEs when CAR-T is not feasible, may represent reasonable options in patients at higher infectious risk, within an individualized and context-dependent treatment strategy.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13282886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148294079","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":"Clinical research progress of menin inhibitors for acute myeloid leukemia: latest updates from the 2025 ASH Annual Meeting.","authors":"Chenchen Ma, Siyuan Cui, Jingyi Wang","doi":"10.1186/s40164-026-00803-2","DOIUrl":"10.1186/s40164-026-00803-2","url":null,"abstract":"<p><p>Menin inhibition has emerged as a promising therapeutic strategy for acute myeloid leukemia (AML) driven by KMT2A rearrangements or NPM1 mutations. Novel menin inhibitors, including revumenib, bleximenib, ziftomenib, and enzomenib, are currently under clinical evaluation, and selected updated clinical results were presented at the 2025 American Society of Hematology (ASH) Annual Meeting. This brief review summarizes the key findings and discusses the emerging clinical questions regarding combination strategies, treatment sequencing, and molecularly defined use of menin inhibitors.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13281606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283540","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":"A multimodal single-cell framework for ecosystem-level profiling of circulating tumor and non-tumor cells.","authors":"Gabriela Felix, Francesca Aguirre, Lisa Zhou, Aaron Denmark, Rocio Alvarez, Daniel M Kim, Jun Gong, Megan P Hitchins","doi":"10.1186/s40164-026-00796-y","DOIUrl":"10.1186/s40164-026-00796-y","url":null,"abstract":"<p><p>Multimodal profiling of circulating tumor cells (CTCs) and non-tumor circulating cells was performed in six patients with advanced colorectal cancer to identify biological programs beyond enumeration-based analyses. Across all patients, we identified 3,981 CTCs characterized by pronounced EpCAM/L1CAM co-expression, variable PD-L1 expression, and low LGR5 expression, consistent with metastatic-associated phenotypes. Integrated single-cell multi-omics analysis of 1,720 cells revealed genomic instability within EpCAM⁺, L1CAM⁺, LGR5⁺, and PD-L1⁺ CTC subsets, including Y-chromosome loss in male patients and marked intra-patient heterogeneity. In parallel, non-CTCs exhibited upregulation of inflammatory and metabolic dysregulation programs. This hypothesis-generating study highlights the relevance of blood-based multimodal single-cell profiling for interrogating tumor-host states beyond insights from CTC enumeration alone.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13281560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283508","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":"Breathing new life into T-cell receptor-engineered T-cell therapy in solid tumors: enhancing strategies to expand the universality of precision therapy.","authors":"Yawen Li, Xiaozhen Zhang, Yan Chen, Jieru Lin, Tingbo Liang, Xueli Bai","doi":"10.1186/s40164-026-00793-1","DOIUrl":"10.1186/s40164-026-00793-1","url":null,"abstract":"<p><p>Adoptive T-cell transfer therapy (ACT) has significantly propelled the advancement of tumor immunotherapy. Among various strategies targeting solid tumors, the T-cell receptor (TCR)-engineered T-cell (TCR-T cell) therapy has emerged as a highly promising approach, exhibiting an expanded therapeutic window across diverse patient populations and superior tumoricidal activity in certain solid malignancies compared with chimeric antigen receptor T cell (CAR-T) and tumor-infiltrating T cells/lymphocyte (TIL) therapies. However, its clinical efficacy remains constrained. In this paper, we introduce the limitations and challenges faced by TCR-T cells in solid tumor treatment, and summarize recent efforts overcoming these limitations and translating TCR-T cell therapies into clinical application. Furthermore, their current status and effectiveness in clinical solid tumor patients were analyzed. We expect that the precision therapies of TCR-T cells, with the support of high-affinity TCRs and a diverse array of target antigens, multimodal synergistic therapy strategies and efficient in vitro production processes, will benefit a wider patient population, thus revealing new clinical application potential.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":" ","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13531875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283548","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":"Overcoming fratricide of CD86 targeting CAR-T cells by defined logic-gate CAR strategy.","authors":"Tobias Riet, Simon Lennartz, Niklas Bösing, Lars Fabian Prinz, Luise Dähn, Christof Scheid, Michael Hallek, Markus Martin Chmielewski","doi":"10.1186/s40164-026-00791-3","DOIUrl":"10.1186/s40164-026-00791-3","url":null,"abstract":"<p><p>Despite its remarkable success in the treatment of several hematological malignancies, cellular immunotherapy using chimeric antigen receptor (CAR) T cells faces significant challenges when treating refractory/relapsed or myeloid malignancies such as AML, CML or multiple myeloma. To overcome the pronounced heterogeneity of such diseases, the search for suitable tumor-associated antigens recently led to surface antigens of the B7 protein family as potential CAR-T cell targets. Using the example of CD86-targeting, we highlight a considerable pitfall of CAR-T therapy which utilizes B7-family proteins as a prominent group of T cell (activation) associated antigens. In a consistent set of in vitro and in vivo experiments we could demonstrate that fratricide among pre-activated CD86-specific CAR-T cells strongly reduces their overall survival and efficacy in tumor killing as recently shown for B7-H3/CD276-targeting CARs. Therefore, we propose a defined combinatorial antigen recognition concept via dual-chain CAR-T cells that incorporate an \"AND-gate\" mechanism through CD19 primary CAR activation and CD86 conditional co-stimulation to circumvent a severely limited outcome.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13281288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148276688","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 the mevalonate pathway with statins overcomes acquired resistance to KRAS^G12C inhibitors in non-small cell lung cancer.","authors":"Weihao Lin, Qi-An Chen, Yannan Yang, Yibo Gao, Jie He","doi":"10.1186/s40164-026-00797-x","DOIUrl":"10.1186/s40164-026-00797-x","url":null,"abstract":"<p><p>The emergence of covalent KRAS^G12C inhibitors has revolutionized the treatment of non-small cell lung cancer (NSCLC), yet acquired resistance remains a major clinical challenge. Here, we systematically identified statins as potent agents capable of overcoming acquired resistance to KRAS^G12C inhibitors through high-throughput screening of 1,971 FDA-approved compounds. Statin treatment preferentially induced cell death in resistant cells, markedly impairing tumor growth both in vitro and in vivo. Proteomic profiling and pathway analysis revealed upregulation of the mevalonate (MVA) pathway in resistant cells. Genetic silencing of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and pharmacologic inhibition of the MVA-geranylgeranyl pyrophosphate (GGPP) branch recapitulated the effects of statins. Mechanistically, MVA-GGPP signaling promoted Yes-associated protein (YAP) activation, whereas disruption of this axis by statins or geranylgeranyl transferase I (GGTase-I) inhibitors impaired YAP-driven transcription and cell survival. Combination therapy with simvastatin and KRAS^G12C inhibitors delayed resistance onset and enhanced antitumor efficacy across multiple in vivo models, with acceptable tolerability. These findings identify the MVA-GGPP-YAP pathway as a therapeutic vulnerability in acquired KRAS^G12C inhibitor resistance and support repurposing statins to improve KRAS^G12C-targeted therapy.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13281582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148276705","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":"Autophagy-promoted immunogenic cell death elicited by tyrosine kinase inhibitor orchestrates a synergistic immunotherapeutic microenvironment in hepatocellular carcinoma.","authors":"Shan-Ru Feng, En-Fu Dong, Zheng Gao, Mo-Ran Xu, Pascal Kwangwari, Cheng-Qiang Sun, Jia-Feng Chen, Ying-Hong Shi, Wei-Ren Liu, Wei-Xun Wu, Xin Zhang, Ao Huang, Xuan-Ming Luo, Qiang Gao, Guo-Ming Shi, Ai-Wu Ke, Jian Zhou, Jia Fan, Xiao-Ying Wang, Jing-Bo Qie, Xiu-Tao Fu, Zhen-Bin Ding","doi":"10.1186/s40164-026-00792-2","DOIUrl":"10.1186/s40164-026-00792-2","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The combination of tyrosine kinase inhibitors (TKIs) like lenvatinib with immune checkpoint inhibitors (ICIs) has become a cornerstone of first-line therapy for advanced hepatocellular carcinoma (HCC). However, this approach faces a significant bottleneck, with objective response rates lingering around 20-36%, largely due to the non-immunogenic (\"cold\") nature of most HCC tumors. This highlights a critical need for strategies that can remodel the tumor immune microenvironment to enhance therapeutic efficacy.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We systematically screened existing TKIs for their ability to induce immunogenic cell death (ICD). ICD hallmarks were validated through multiple assays in HCC cell lines and patient-derived organotypic tumor spheroids (PDOTS) from 20 primary and 15 neoadjuvant-treated HCC samples. Mechanistic studies employed RNA-seq, pharmacological inhibitors, and genetic knockdown approaches. A tumor cell-Bone Marrow-Derived Dendritic Cells (BMDC)-CD8&lt;sup&gt;+&lt;/sup&gt; T cell triple co-culture system was established for functional assays. In vivo efficacy was evaluated in subcutaneous and orthotopic mouse models. Tumor immune profiling was performed using Cytometry by Time-Of-Flight (CyTOF), multiplex immunofluorescence, and spatial proximity analysis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Among screened TKIs, anlotinib emerged as the most potent ICD inducer, triggering extracellular ATP release, HMGB1 secretion, and surface calreticulin exposure. RNA-seq and GSEA identified ER stress and autophagy as top enriched pathways. Mechanistically, anlotinib inhibited FGFR-1 phosphorylation, activating ER stress (upregulation of CHOP/ATF4 with ATF4 nuclear translocation) and secondary autophagy (LC3-II conversion). Pharmacological inhibition of ER stress or autophagy, as well as ATG5/LC3B knockdown, abrogated damage-associated molecular patterns (DAMPs) release, confirming autophagy's essential role in ICD execution. Luminex cytokine assay and mass spectrometry identified the key secretome (CCL19, CXCL12) and DAMPs essential for dendritic cell recruitment. In BMDC co-culture experiments, anlotinib-conditioned media enhanced DC migration (blocked by anti-HMGB1), DC activation (CD86/CD40 upregulation), and subsequent CD8&lt;sup&gt;+&lt;/sup&gt; T cell priming (CD25/CD69/IFN-γ expression). In vivo, anlotinib inhibited tumor growth, enhanced CD8&lt;sup&gt;+&lt;/sup&gt; T cell and dendritic cell infiltration, and increased spatial interactions between ICD&lt;sup&gt;+&lt;/sup&gt; tumor cells and T cells. Anlotinib synergized with anti-PD-1 therapy, an effect mediated by CD8&lt;sup&gt;+&lt;/sup&gt; T cells and DCs. Genetic (shATG5) or pharmacological (3-MA) autophagy inhibition significantly attenuated anlotinib's antitumor efficacy, while autophagy enhancement through ATG5 overexpression or metformin potentiated it. The triple combination of anlotinib, anti-PD-1, and metformin achieved the highest levels of HMGB1 release and immune cell infiltration and maximal tumo","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":" ","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13536651/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148263855","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}