Biomarker Research最新文献

{"title":"Targeting myeloid cell plasticity and metabolic reprogramming to alleviate T cell dysfunction and exhaustion-associated states and enhance immune checkpoint blockade therapy.","authors":"Mingxing Wang, Jian Chen, Zhonghua Wu, Zhiying Wang, Zhixian Zhong, Yi Zhong","doi":"10.1186/s40364-026-01011-0","DOIUrl":"10.1186/s40364-026-01011-0","url":null,"abstract":"<p><p>Immune checkpoint blockade (ICB) therapy has achieved clinical progress in various malignancies, yet primary and acquired resistance limits its efficacy in solid tumors. Myeloid cells in the tumor microenvironment (TME), including tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), and myeloid-derived suppressor cells (MDSCs), undergo metabolic reprogramming under hypoxia and nutrient stress. They impair effector T cell function and may contribute to exhaustion-associated states via nutrient competition, release of toxic metabolites, and formation of physical barriers, representing a critical resistance mechanism. This review summarizes the spatiotemporal heterogeneity of myeloid cells and the metabolic networks underlying their immunosuppressive phenotypes, focusing on dysregulated lipid and cholesterol metabolism, amino acid remodeling, the glycolytic switch, and subcellular stress responses. We analyze how metabolic dysregulation causes T cell dysfunction and, in defined contexts, contributes to exhaustion-associated transcriptional programs through nutrient competition, toxic metabolite accumulation, and upregulation of inhibitory receptor ligands, and summarize intervention strategies targeting myeloid recruitment, phenotypic remodeling, metabolic reprogramming, and pathological structures combined with ICB. We discuss challenges of efficacy heterogeneity and safety in clinical translation, and highlight the prospects of multi-omics and computational biology in guiding next-generation combination immunotherapy. Understanding myeloid metabolic plasticity may provide a basis for overcoming immunotherapy resistance and establishing precise synergistic strategies.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149208119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ubiquitin signaling in tumor-associated macrophage reprogramming: mechanisms and therapeutic opportunities in cancers.","authors":"Xudong Li, Yaomei Wang, Ruochen Xu, Ziheng Qian, Meimei Yan, Mengya Gao, Zexing Liu, Yun Zhai, Lijie Wang, Yushan Cui, Lina Liu, Yongping Song, Zhilei Bian, Linping Xu, Wei Li, Baijun Fang","doi":"10.1186/s40364-026-01020-z","DOIUrl":"10.1186/s40364-026-01020-z","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) are key regulators of tumor progression and immune suppression within the tumor microenvironment (TME). Emerging evidence identifies ubiquitination, a dynamic post-translational modification that regulates protein stability, localization, and signaling activity, as a critical determinant of TAM function. Ubiquitin signaling orchestrates macrophage inflammatory responses, metabolic reprogramming, and tumor cell-immune cell crosstalk through coordinated actions of ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, ubiquitin-protein ligases (E3s), and deubiquitinating enzymes (DUBs). Dysregulation of these ubiquitin networks fosters an immunosuppressive microenvironment, thereby promoting tumor growth, metastasis, and therapeutic resistance. In this review, we summarize recent advances in the role of ubiquitination in TAM biology, focusing on key E3 ubiquitin ligases and DUBs in TAM immunity. We further discuss emerging ubiquitin-dependent signaling pathways that integrate metabolic and inflammatory cues within TAMs. Finally, we highlight the therapeutic potential of targeting ubiquitination machinery to reprogram TAMs and remodel the TME. Collectively, this review provides a comprehensive framework for understanding ubiquitin-mediated regulation of TAM function and offers novel perspectives for developing ubiquitination-based cancer immunotherapies.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149208204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peripheral blood CXCL1 serves as a non-invasive dynamic biomarker for intratumoral colonization of attenuated Salmonella.","authors":"Leyang Wu, Liyuan Qiao, Xinyue Qiao, Wanru Wang, Chengxuan Lei, Ying Sun, Xiao Dong, Jiayi Yu, Chenyang Li, Zengzheng Du, Jing Tian, Mengyu Liu, Heng Liu, Zichun Hua","doi":"10.1186/s40364-026-01017-8","DOIUrl":"10.1186/s40364-026-01017-8","url":null,"abstract":"<p><p>Attenuated oncolytic bacteria represent a promising targeted delivery platform for cancer therapy; however, the lack of non-invasive biomarkers to monitor their persistent intra-tumoral colonization severely limits clinical translation, efficacy assessment, and safety monitoring. Here, we identify the sustained elevation of peripheral blood CXCL1 as a dynamic, non-invasive biomarker for the persistent colonization of attenuated Salmonella in solid tumors. Across four orthotopic preclinical models (including lung, breast, and bladder cancers, as well as melanoma), effective bacterial colonization specifically drove prolonged systemic CXCL1 elevation. Focusing specifically on the melanoma model, rapid bacterial eradication via intratumoral antibiotics restored CXCL1 to baseline. Furthermore, comparisons with a colonization-deficient mutant strain confirmed that CXCL1 elevation strictly depends on intra-tumoral, rather than systemic, bacterial burden. Mechanistically, single-cell RNA sequencing (scRNA-seq) revealed that tumor-colonizing bacteria profoundly reshape the tumor microenvironment by directly activating and recruiting neutrophils, monocytes, and cancer-associated fibroblasts (CAFs), which act as the primary cellular sources of CXCL1 production and systemic leakage. These findings highlight peripheral blood CXCL1 as a robust and actionable biomarker for real-time monitoring of oncolytic bacterial colonization, providing crucial guidance for dosing optimization and biosafety evaluation in clinical applications.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149208135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Persistent CAR-T donor cells contribute to mixed chimerism with cytopenia after CAR-T-bridged allo-HSCT: rescue by CAR-target-knockout DLI in three cases.","authors":"Yi Liu, Zelin Wang, Yamei Wu, Xiuwen Xu, Xiaoxia Hu, Jing Pan","doi":"10.1186/s40364-026-01021-y","DOIUrl":"10.1186/s40364-026-01021-y","url":null,"abstract":"<p><p>Persistent CAR-T donor cells after CAR-T-bridged allogeneic hematopoietic stem cell transplantation (allo-HSCT) may complicate hematopoietic recovery. When CAR-T and HSCT cells share the same donor, standard donor chimerism cannot distinguish their contributions. We report three patients with relapsed/refractory T-cell malignancies who received CAR-T and allo-HSCT from distinct donors, enabling three-party short tandem repeat (STR) analysis to resolve CAR-T donor, HSCT donor, and recipient compartments. Patient 2, with detectable residual CAR transgene at transplantation (240 copies/µg gDNA), developed mixed chimerism with cytopenia (MCC) and a CAR-T donor contribution of 47.72%. Patient 3, also with detectable residual CAR transgene (22,162 copies/µg gDNA), developed mixed chimerism, with a CAR-T donor contribution of 14.23%. In contrast, Patient 1, with undetectable CAR transgene at transplantation, showed stable complete donor chimerism (CDC) and hematopoietic recovery. Guided by the two-step reconstitution pattern observed in Patient 1, we administered CAR-target-knockout donor lymphocyte infusion (KO-DLI) as rescue treatment in Patient 2 and preemptive intervention in Patient 3. Both eventually became CAR-undetectable, with restoration of CDC and hematologic recovery, although the independent effect of KO-DLI could not be isolated. All three remain in complete remission (follow-up + 713, +335, + 201 days). Residual CAR transgene at transplantation may serve as an early risk signal for CAR-T donor cell persistence, and KO-DLI warrants prospective validation as a transplantation-sparing salvage approach.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149208106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic regulation of H3K9 modifications in cancer: pathogenesis and targeted therapies.","authors":"Yuanyuan Xu, Qihui Wu, Yuxiu Zhang, Jitong Zhao, Xiaodan Fu, Anqi Li, Yimin Li","doi":"10.1186/s40364-026-01019-6","DOIUrl":"10.1186/s40364-026-01019-6","url":null,"abstract":"<p><p>Post-translational modifications (PTMs) of histone H3 at lysine 9 (H3K9) contribute to chromatin homeostasis and transcriptional regulation and have been implicated in cancer progression. However, how distinct H3K9 modification states differ in function, compete for the same lysine residue, and dynamically respond to cellular context remains incompletely understood. This review summarizes the biochemical characteristics and enzymatic regulation of H3K9 methylation, acetylation, and non-acetyl acylations, including lactylation, β-hydroxybutyrylation, butyrylation, and crotonylation. We examine their roles in DNA replication, transcription, and DNA damage repair, as well as their interplay with other epigenetic regulatory mechanisms. We further discuss how H3K9-associated regulatory networks contribute to tumor proliferation, stemness maintenance, metabolic reprogramming, invasion and metastasis, immune microenvironment remodeling, therapeutic resistance, and programmed cell death, emphasizing their context-dependent and, in some settings, opposing biological effects. Finally, we evaluate preclinical and clinical advances in pharmacologically targeting H3K9-associated regulatory enzymes, distinguishing residue-specific mechanistic evidence from broader enzyme-level effects, and outline future directions for biomarker-guided epigenetic therapies in cancer.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149208110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-in-human phase Ia study of the covalent TEAD palmitoylation inhibitor BPI-460372 in patients with advanced solid tumors: pharmacokinetics, exposure-limited dosing, and early antitumor activity.","authors":"Hongge Liang, Yan Xu, Jing Zhao, Xiaoyan Liu, Wei Zhong, Xin Zheng, Hongzhong Liu, Minjiang Chen, Xiaohong Han, Mengzhao Wang","doi":"10.1186/s40364-026-01012-z","DOIUrl":"10.1186/s40364-026-01012-z","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The Hippo pathway is a critical regulator of tumor development and progression, dysregulation of the Hippo pathway drives tumorigenesis in multiple malignancies. BPI-460,372 is a first‑in‑class covalent irreversible inhibitor of transcriptional enhanced associated domain (TEAD) palmitoylation. This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of BPI-460,372 in patients with advanced solid tumors.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This open-label, multicenter, single-arm phase Ia dose-escalation study enrolled patients with advanced solid tumors who had progressed after standard therapies or lacked available standard treatment options. A modified 3 + 3 design with accelerated titration was used. BPI-460,372 was administered orally once daily under fasting conditions, with dose escalation from 10 mg to 240 mg daily. Additional cohorts evaluated twice-daily dosing (80 mg and 120 mg) and postprandial administration (80 mg and 160 mg) to characterize exposure optimization strategies. Primary endpoints were safety, tolerability, dose-limiting toxicities (DLTs), and the maximum tolerated dose (MTD). Secondary endpoints included pharmacokinetics (PK) and preliminary antitumor efficacy. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; modified criteria were applied for malignant pleural mesothelioma.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Between April 2023 and December 2024, 36 patients were screened, and 28 patients were enrolled and treated. No DLTs were observed, and the MTD was not reached. All patients experienced at least one treatment-emergent adverse event (TEAE). Treatment-related adverse events (TRAEs) occurred in 89.3% of patients, with grade ≥ 3 events occurring in 39.3%. Proteinuria was the most common TRAE (46.4%, including 10.7% grade ≥ 3). Three deaths occurred during the study, including one treatment-related death due to abdominal infection. Pharmacokinetic analyses demonstrated rapid absorption, dose-dependent increases in exposure, achievement of steady-state exposure after repeated dosing, and limited drug accumulation. Among 28 evaluable patients, one confirmed partial response (PR) was observed in the 120 mg twice-daily cohort. The objective response rate (ORR) and disease control rate (DCR) were 3.6% (95% CI: 0.1-18.4) and 64.3% (95% CI: 44.1-81.4), respectively. Median progression-free survival (PFS) was 5.6 months (95% CI: 2.4-7.0), and median overall survival (OS) was 13.2 months (95% CI: 7.4-15.1).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;BPI-460,372 demonstrated a distinct pharmacokinetic profile and showed preliminary antitumor activity in patients with advanced solid tumors. However, treatment-emergent toxicities and exposure limitations constrained further dose escalation and prevented definition of an optimal biologically active dose. These findings support further clinical eval","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA N4-acetylcytidine modification in health and cancer: molecular mechanisms, cellular plasticity, and therapeutic opportunities.","authors":"Xiao-Yan He, Kang Du, Chaofu Yue, Chongxin Li, Yunze Zhu, Yuan Tang, Hanmin Wang, Mei Yang, Fei He, Xiulin Jiang","doi":"10.1186/s40364-026-01014-x","DOIUrl":"10.1186/s40364-026-01014-x","url":null,"abstract":"<p><p>N⁴-acetylcytidine (ac⁴C) is an evolutionarily conserved RNA modification that was initially identified in transfer RNA (tRNA) and ribosomal RNA (rRNA). Increasing evidence has subsequently expanded its functional landscape to messenger RNA (mRNA) and multiple classes of non-coding RNAs (ncRNAs). As the best-characterized ac⁴C writer in mammals, N-acetyltransferase 10 (NAT10) orchestrates RNA structure, stability, processing, and translation, thereby governing fundamental physiological processes, including ribosome biogenesis, translational fidelity, proteostasis, cell fate determination, hematopoiesis, reproduction, and embryonic development. Cancer cells exploit the NAT10-ac⁴C axis to selectively stabilize or enhance the translation of oncogenic transcripts, reprogram tRNA and rRNA-dependent translational programs, and cooperate with non-canonical NAT10 functions, including R-loop regulation, protein acetylation, and RNA binding, to sustain uncontrolled proliferation, cancer stemness, metabolic reprogramming, DNA damage repair, invasion and metastasis, resistance to regulated cell death, and immune evasion. Consequently, the NAT10-ac⁴C axis has emerged as a central molecular hub linking RNA fate, the translational machinery, and adaptive tumor reprogramming. Therefore, phenotypes resulting from NAT10 depletion or pharmacological inhibition should not be indiscriminately attributed to reduced ac⁴C deposition in the absence of catalytic rescue experiments and site-specific validation. In this Review, we comprehensively summarize the molecular basis of ac⁴C, its substrate landscape, catalytic mechanisms, and determinants of substrate selectivity, as well as its physiological functions in normal tissues and pathological roles in cancer. We further compare the shared and context-dependent mechanisms by which the NAT10-ac⁴C axis drives malignant progression and therapeutic resistance across diverse cancer types. In addition, we critically evaluate current ac⁴C detection technologies, the hierarchy of substrate evidence, NAT10 inhibitors, targeted protein degradation strategies, rational combination therapies, biomarker-guided patient stratification, and therapeutic windows. Finally, we propose that future research should move beyond broad NAT10 inhibition toward identifying tumor-specific NAT10 dependencies and selectively disrupting oncogenic NAT10-RNA regulatory circuits through high-confidence ac⁴C atlases, site-specific RNA editing technologies, and precision delivery strategies.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The immune phenotype of circulating tumor cells: from escape mechanisms to immunotherapy navigation.","authors":"Pengfei Zhang, Miao Li, Lixin Li, Jiahao Fu, Qiang Li, Tianxing Liu, Renya Zeng, Yang Zhou, Rudi Mao, Xiaolong Wang, Shuhui Li, Xinyu Zhang, Zhe Yang","doi":"10.1186/s40364-026-01015-w","DOIUrl":"10.1186/s40364-026-01015-w","url":null,"abstract":"<p><p>Circulating tumor cells (CTCs) must survive immune attack in the bloodstream before they can contribute to distant metastasis. Their immune phenotype, including checkpoint ligands, antigen-presentation molecules, and immunomodulatory features, can be assessed through serial blood sampling and may provide information complementary to established immunotherapy biomarkers. This review organizes CTC immune evasion across intravasation, circulatory transit, and colonization, and examines CTC-associated immune interactions while distinguishing direct CTC observations from evidence derived from tumor tissue, cell culture, or animal models. We review technologies for immune phenotyping and the clinical evidence linking CTC immune features to immunotherapy outcomes across cancer types. Current studies support further investigation of longitudinal CTC monitoring, but heterogeneous assays, small or retrospective cohorts, and limited prospective validation prevent routine treatment selection based on these readouts. We also discuss experimental approaches to disrupting CTC immune protection during vascular transit and outline a four-stage pathway from discovery and analytical validation to clinical utility and implementation. CTC immune phenotyping remains a research strategy whose clinical value must be established beyond tissue biomarkers, ctDNA, and standard clinical assessment.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The NFIL3-MYC signaling axis: a novel therapeutic target and prognostic marker in high-risk multiple myeloma.","authors":"Daniela Simone Maichl, Wen-Hui Cheng, Poonam Kumari, Julius Arthur Kirner, Stefanie Schmidt, Carsten Patrick Ade, Mengshi Yang, Malik Salman Haider, Yuquan Chi, Robert Luxenhofer, Lyudmyla Taranets, Melanie Haffner-Luntzer, Verena Fischer, Anita Ignatius, Ellen Leich, Gerardo Zapata, Nikita Popov, Franziska Jundt","doi":"10.1186/s40364-026-01018-7","DOIUrl":"10.1186/s40364-026-01018-7","url":null,"abstract":"<p><strong>Background: </strong>Drug resistance causes tumor relapse, limits the outcomes of patients with high-risk multiple myeloma (MM), and requires the development of targeted therapeutics. Increased Notch signaling promotes drug resistance in high-risk del(17p)/TP53-deficient clonogenic MM cells, highlighting the pathway and its downstream effectors as rational therapeutic targets in aggressive MM. However, the identification of selective, safe, and efficacious inhibitors targeting the Notch pathway remains a substantial challenge.</p><p><strong>Methods: </strong>To identify novel druggable Notch effectors, we performed transcriptome profiling of Notch-depleted MM cells and selected potential candidates. We applied functional high-throughput shRNA library screens targeting these genes in MM cells with high Notch activity and under drug selection. Through bioinformatic analysis, we selected NFIL3 and validated its mechanistic specificity using ChIP-seq analysis, immunoblotting, cell viability and growth assays. We targeted NFIL3 via the oleanane-type triterpenoid saponin Raddeanin A (RA) and tested its efficacy in vivo using the murine MOPC.315.BM.Luc.eGFP-mCrbn^I391V model. To improve efficacy of RA in vivo, we developed drug-loaded nanocarriers based on polymer micelles. Using patient MM cells with high-risk cytogenetic abnormalities and post B-cell maturation antigen (BCMA)-directed immunotherapy, we demonstrated efficacy of RA to circumvent multi-drug resistance. To determine the prognostic significance of NFIL3, we correlated its transcriptional expression with survival data and cytogenetic abnormalities of two patient cohorts.</p><p><strong>Results: </strong>In functional genomics screens, we identified NFIL3 as a critical therapeutic vulnerability in high-risk, multidrug-resistant MM. Mechanistic studies silencing NFIL3 revealed that NFIL3 acts as a repressor of the MYC oncogenic driver in MM cells. RA collapsed the MYC-driven transcriptional program essential for MM cell survival and abrogated multidrug resistance of human and murine MM cells in vitro and in vivo. Importantly, the drug RA demonstrated potent anti-myeloma activity in patient-derived cells with high-risk cytogenetics following failure of BCMA-directed immunotherapies. Furthermore, high NFIL3 expression was associated with high-risk cytogenetic abnormalities and extramedullary disease and was verified as an independent prognostic marker for overall survival in MM patients.</p><p><strong>Conclusions: </strong>RA targets the NFIL3-MYC axis and demonstrates potent anti-myeloma activity in vivo and in patient-derived high-risk MM cells following failure of BCMA-directed immunotherapies, providing a potent salvage strategy for multi-refractory disease.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond a cancer stem cell marker: molecular state dependent functions of CD133 and state targeted therapy.","authors":"Lin Cheng, Jingyan Wang, Yaqiong Liu, Timothy O'Brien, Janusz Krawczyk, Laura Barkley, Shanye Yin, Sanbing Shen, JunPeng Li, Sifang Zhang","doi":"10.1186/s40364-026-01013-y","DOIUrl":"10.1186/s40364-026-01013-y","url":null,"abstract":"<p><p>CD133 (prominin-1) is among the most widely used cancer stem cell markers, yet two decades of research have yielded persistent contradictions: CD133-negative cells can be tumorigenic, CD133-positive and -negative states can interconvert, and CD133 perturbation produces opposing phenotypes across models, while CD133 directed therapies have encountered toxicities consistent with on-target/off-tumor effects. We propose that these inconsistencies share a common origin: CD133 positivity does not define a homogeneous functional entity. Rather, the functional identity of CD133 is jointly encoded by PROM1 alternative splicing, post translational modification combinations, and subcellular localization. Depending on this molecular state, the same protein can support stemness, drive migration and invasion, sustain quiescence like states, suppress autophagy, or be exported as vesicular signals that remodel the tumor microenvironment. CD133 is therefore better understood not as a static marker with a fixed function, but as a state dependent functional integrator, in which detected expression need not reflect pathogenic function. This distinction matters therapeutically: eliminating CD133-positive cells and disrupting pathogenic CD133 states are not equivalent objectives. CD133 directed therapy should accordingly shift from marker targeting to state targeting, guided by a state resolved stratification scheme that matches isoform-, phosphorylation-, glycosylation- and localization- defined CD133 states to rational interventions.</p>","PeriodicalId":54225,"journal":{"name":"Biomarker Research","volume":"14 1","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13651184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}