Clinical and Translational Medicine最新文献

{"title":"Spatial-EV-seq: Mapping the spatial organisation of extracellular vesicles in tissues","authors":"Xing Xu, Qianxi Wen, Yanling Song, Chaoyong Yang","doi":"10.1002/ctm2.70825","DOIUrl":"10.1002/ctm2.70825","url":null,"abstract":"<p>Extracellular vesicles (EVs) are increasingly recognised as promising biomarkers for cancer diagnosis, immunotherapy response prediction, and disease monitoring.<span><sup>1, 2</sup></span> Their ability to carry bioactive molecules, including proteins, nucleic acids, and lipids, from parent to recipient cells positions them as critical mediators of intercellular communication. Yet despite this potential, translating EV biology into clinical utility has been hampered by a fundamental limitation: conventional EV analysis relies on tissue dissociation and differential centrifugation, which destroy the spatial architecture of EVs and erase their native distribution, interaction networks, and connections with parent and recipient cells.<span><sup>3</sup></span> The result is a loss of contextual information about where EVs reside, which cells they interact with, and how their location shapes their function.<span><sup>4</sup></span></p><p>Spatial transcriptomics has transformed tissue analysis by preserving spatial context while profiling gene expression.<span><sup>5, 6</sup></span> But a similar approach for EVs has been conspicuously absent. This gap matters clinically. A growing body of evidence suggests that the location of EVs within tissues is not merely a passive variable but an active determinant of their biological roles. EVs from tumour surfaces carry molecular signatures distinct from those in adjacent tissues, and their spatial heterogeneity reflects disease progression and therapeutic response. To capture this dimension, we developed Spatial-EV-seq,<span><sup>7</sup></span> a method for in situ spatial profiling of EVs within their native microenvironmental context.</p><p>The technology operates through three integrated steps (Figure 1). First, an antibody-engineered capture interface immobilises EVs directly from tissue sections via a blotting-based transfer strategy, preserving their original spatial coordinates with minimal lateral displacement (approximately 5.8 µm) and a recovery rate of 60% to 70%. Second, captured EVs are amplified by rolling circle amplification using EV surface-binding aptamers, enabling fluorescence imaging of individual EVs at approximately 1 µm resolution. Third, by integrating these spatial EV maps with spatial transcriptomics<span><sup>8</sup></span> on adjacent sections, the method resolves location-specific EV-cell communication networks, linking EV position, molecular identity, and neighbouring cellular states in a single analytical framework.</p><p>Applying Spatial-EV-seq to an anti-PD1-treated breast cancer mouse model, we uncovered a spatially orchestrated immunosuppressive axis. PDL1<sup>+</sup> EV-enriched zones correlated with CD8<sup>+</sup> T cell exhaustion, establishing immune-privileged niches, whereas PDL1<sup>+</sup> EV-depleted regions preserved immunocompetence and therapeutic sensitivity. Notably, regions with high PDL1<sup>+</sup> EV abundance but low CD274 gene expression indicated th","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13528617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863750","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":"Beyond immune activation: Nitric oxide-mediated tumour microenvironment remodeling operates as a new paradigm for cancer immunotherapy","authors":"Xie Xinxin, Xu Shuyu, Liang Xiaolong","doi":"10.1002/ctm2.70794","DOIUrl":"10.1002/ctm2.70794","url":null,"abstract":"<p>Cancer immunotherapy has fundamentally revolutionized oncology by harnessing the host immune system to eradicate malignant cells. Immune checkpoint blockade (ICB), particularly antibodies targeting the PD-1/PD-L1 axis, has achieved remarkable clinical success across a spectrum of cancer types.<span><sup>1</sup></span> However, durable responses remain restricted to a minority of patients, notably those with immunologically ‘cold’ tumours. Accumulating evidence indicates that therapeutic resistance stems not merely from a deficit in immune activation, but rather from a hostile tumour ecosystem governed by aberrant vasculature, severe hypoxia, physical immune exclusion and profound immunosuppression. Consequently, the next generation of cancer immunotherapy demands a conceptual evolution: transitioning from the conventional focus on single-cell immune activation toward the active remodeling of the tumour microenvironment (TME) to engineer an immune-permissive ecosystem.</p><p>Nitric oxide (NO), a small and highly reactive signalling molecule, has long been appreciated for its diverse biological repertoire, ranging from vascular tone regulation to immune modulation and cytotoxicity. Historically, NO was predominantly investigated as a direct antitumour agent capable of inducing lethal oxidative and nitrosative stress. Yet, emerging insights reveal that the functional scope of NO extends far beyond direct tumoricidal activity. Governed by its concentration, spatial localization and exposure kinetics, NO acts as a master regulatory signal that orchestrates multiple components of the tumour ecosystem (Figure 1). This paradigm shift raises a compelling biological question: can NO be successfully repositioned from a fleeting cytotoxic weapon into a programmable architect of the TME?</p><p>Despite its immense therapeutic potential, the clinical translation of NO has long been thwarted by intrinsic pharmacological hurdles, notably its transient half-life, rapid diffusion kinetics, and the impossibility of achieving sustained, localized intratumoral production. Traditional delivery modalities—such as small-molecule donors and advanced nanomaterials—have sought to mitigate these limitations, yet they consistently fail to achieve precise spatiotemporal control.<span><sup>2</sup></span> Recent breakthroughs in synthetic biology offer a transformative solution by converting NO from a transient chemical mediator into a programmable therapeutic cue.</p><p>The development of engineered microorganisms capable of sustained intratumoral NO production provides a compelling proof-of-concept for this strategy.<span><sup>3, 4</sup></span> By rewiring bacterial metabolism towards endogenous NO synthesis, engineered microbes can function as localized ‘living factories’ that continuously generate NO within the tumour niche. Rather than relying on direct tumour cell lysis, these NO-producing bacteria reshape the tumour ecosystem through the coordinated, multi-target regul","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13528614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863711","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":"Cancer cell-selective ectopic expression of CD20 as an antigen enables rituximab repurposing for solid tumour immunotherapy","authors":"Ziyan Kong,&nbsp;Yile Wang,&nbsp;Yunqi Zhao,&nbsp;Lu Wang,&nbsp;Zhimin Fan,&nbsp;Yongqian Shu,&nbsp;Jinke Wang","doi":"10.1002/ctm2.70804","DOIUrl":"10.1002/ctm2.70804","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Despite the clinical success of cancer immunotherapies, their efficacy is often compromised by antigen-related problems, including downregulation, loss, and off-tumour toxicity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>To overcome these limitations that challenge the current immunotherapies dependent on native antigens, we here describe a new cancer immunotherapy strategy that artificially and specifically expresses a clinically validated antigen on variant tumours and thus repurposes clinical antibody drugs to treat cancers not belonging to their indications. To authenticate the strategy, we delivered a CD20 gene under the control of an NF-κB-specific promoter to tumours by adeno-associated virus and then treated them with a CD20 antibody, rituximab.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that CD20 was selectively expressed in tumours, and subsequent rituximab treatment engaged multiple antibody-dependent effector mechanisms, including NK-cell-mediated ADCC and macrophage-mediated ADCP. We demonstrated that this strategy is effective not only in variant-cultivated cancer cells, HCT116 spheroids, and patient-derived organoids of human colorectal cancer, but also in a humanized mouse with an HCT116 xenograft and immunocompetent mouse with an MC38 transplant. The strategy showed high cancer cell specificity in both in vitro and in vivo models, resulting in high therapeutic efficacy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This strategy thus creates a new modality of cancer immune-redirection therapy by repurposing both the clinically validated antigen and antibody.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>TRAP enables tumour-selective ectopic expression of the clinically validated antigen CD20, overcoming antigen limitations in solid tumour immunotherapy.</li>\u0000 \u0000 <li>TRAP repurposes anti-CD20 antibodies to engage diverse immune effector mechanisms, including ADCC, ADCP, and CDC.</li>\u0000 \u0000 <li>TRAP demonstrates antitumour efficacy across cellular, 3D tumour spheroid, patient-derived organoid, and in vivo solid tumour models.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13528618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863757","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":"RNA programming towards predictable control of living bacterial therapeutics","authors":"Na Li,&nbsp;Shengkun Tong,&nbsp;Lijie Yin,&nbsp;Yaojie Gao,&nbsp;Yaojun Tong","doi":"10.1002/ctm2.70813","DOIUrl":"10.1002/ctm2.70813","url":null,"abstract":"&lt;p&gt;Engineered bacteria are emerging as living medicines that reach diseased tissues, sense local cues and produce therapeutics in situ.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; Yet their capacity to proliferate and adapt complicates therapeutic control: selective tumour colonisation does not guarantee selective treatment, and bacterial abundance and payload production can vary across lesions. The translational challenge is therefore to predict not only where therapeutic bacteria localise, but also when they activate and what local therapeutic exposure they generate.&lt;/p&gt;&lt;p&gt;Most current circuits address activation through transcriptional regulation. Tumour-associated signals can be connected to inducible promoters, while externally applied energy provides an orthogonal means of controlling therapeutic expression.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Quorum-sensing modules can further provide population-dependent activation once bacterial density reaches a critical threshold.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; In our ongoing development of an &lt;i&gt;Escherichia coli&lt;/i&gt; Nissle 1917 platform, we are integrating tumour-associated lactate sensing with an acyl-homoserine-lactone-dependent population signal. The resulting AND gate is intended to initiate therapeutic expression only when both pathological and population criteria are satisfied, thereby separating physical localisation from functional activation.&lt;/p&gt;&lt;p&gt;Yet transcriptional logic alone does not determine therapeutic output. Promoter strength is commonly inferred from accumulated fluorescence under well-mixed laboratory conditions, implicitly treating transcription, RNA stability, translation and protein accumulation as one process. In vivo, nutrient limitation, oxygen tension, pH, growth rate and host-derived stress can all alter the relationship between promoter activity and final payload exposure. This becomes particularly important when a living therapeutic coordinates multiple effectors with distinct exposure-response relationships, such as cytotoxic proteins, cytokines and metabolites.&lt;/p&gt;&lt;p&gt;Our recently developed SONAR (synthetic orthogonal nucleic acid activation and repression) system provides a programmable RNA-control layer for addressing this gap.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Attenuated Cas13d variants and rationally designed CRISPR RNAs enable transcript degradation, translation repression and IF3-assisted translation activation using a single RNA-guided effector. CRISPR RNA arrays further support compact, multiplexed regulation of individual open reading frames within polycistronic transcripts. In living therapeutics, transcriptional circuits could determine whether a program begins, while RNA-level regulators tune its magnitude, duration and composition. Importantly, this architecture could decouple sensor calibration from payload calibration: once a disease-sensing logic circuit is established, individual therapeutic outputs could be retuned through crRNA design without rebuilding the upstream sensing module. A potent c","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13528621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863755","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":"Reprogramming rather than depleting immunity: Targeting the CD38–NAD+ axis in antibody-mediated autoimmunity","authors":"Huiyuan Li,&nbsp;Jun Wei,&nbsp;Lei Zhang","doi":"10.1002/ctm2.70808","DOIUrl":"10.1002/ctm2.70808","url":null,"abstract":"&lt;p&gt;Autoimmune diseases are driven by aberrant immune responses, but effective immunity is also essential for host defence, immune memory and tissue homeostasis. Their treatment therefore faces a persistent dilemma: How to suppress pathogenic immunity without compromising protective immune function. Corticosteroids and conventional immunosuppressants control disease largely through broad immune inhibition, whereas B-cell- and plasma-cell-directed therapies provide greater cellular selectivity but still deplete immune-cell compartments that also support normal humoral immunity. &lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Repeated or prolonged B-cell depletion is manifested with persistent hypogammaglobulinemia, recurrent infections, impaired vaccine responses and immunoglobulin replacement in some patients. &lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; The unmet need is therefore not simply for stronger immunosuppression but for strategies that selectively attenuate disease-driving immune functions while preserving immune competence. Because immune-cell pathogenicity reflects not only cellular identity but also plastic functional states, reprogramming these states may offer an alternative to cell depletion. Immunometabolic pathways are particularly attractive in this regard, as they directly shape immune-cell activation and effector function. &lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Plasma-cell depletion provided the original rationale for targeting CD38 in immune thrombocytopenia (ITP), with the expectation that eliminating antibody-secreting cells would reduce pathogenic autoantibody production. However, both our investigator-initiated study and the subsequent randomised controlled trial showed that anti-CD38 treatment induced platelet recovery within days, beginning as early as day 3. &lt;span&gt;&lt;sup&gt;5, 6&lt;/sup&gt;&lt;/span&gt; Such rapid kinetics appeared difficult to explain solely by plasma-cell depletion and reduced autoantibody production. This temporal pattern therefore raised a broader mechanistic question: Might CD38 regulate not only the source of pathogenic antibodies but also the downstream effector phase of platelet destruction? Building on this clinical observation, our recent study delineated a CD38–nicotinamide adenine dinucleotide (NAD⁺)–macrophage differentiation axis and tested oral nicotinamide mononucleotide (NMN) as a non-depleting strategy to therapeutically modulate this axis in ITP (Figure 1).&lt;/p&gt;&lt;p&gt;In antibody-mediated ITP, autoantibodies opsonise platelets and promote their clearance, whereas splenic macrophages act as key effectors by recognising and phagocytosing these opsonised platelets via activating Fcγ receptors, particularly FcγRI and FcγRIII.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Beyond its established expression on plasma cells, CD38 is also a major NAD&lt;sup&gt;+&lt;/sup&gt; hydrolase whose upregulation in inflammatory macrophages drives NAD&lt;sup&gt;+&lt;/sup&gt; consumption and inflammatory programmes. &lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; The study linked the CD38-mediated NAD&lt;sup&gt;+&lt;/sup&gt; metabolism to macroph","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13528615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863764","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":"CDO1 as a prognostic biomarker and therapeutic target in gastric cancer: Mechanistic insights into the PI3K/AKT-THBS1 axis and epigenetic reactivation by decitabine","authors":"Fazhi Wang,&nbsp;Runkai Zhou,&nbsp;Jinfeng Cai,&nbsp;Jiazhe Wen,&nbsp;Abudushalamu Yalikun,&nbsp;Yang Yu,&nbsp;Yugang Wen","doi":"10.1002/ctm2.70784","DOIUrl":"10.1002/ctm2.70784","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;As a pivotal metabolic enzyme, cysteine dioxygenase type 1 (CDO1) exerts tumour-suppressive effects across diverse tumour types, and its expression is strongly correlated with clinical prognosis. However, the molecular mechanisms underlying CDO1-mediated tumour suppression in gastric cancer (GC), its relationship with the tumour-associated immune microenvironment, and pharmacological strategies to restore its expression remain poorly understood.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;CDO1 expression and prognosis were evaluated by multi-omics and tissue microarray analyses. Tumour microenvironment and immune infiltration were analyzed using ESTIMATE and ssGSEA. Downstream pathways and interacting proteins were identified by transcriptomics, co-immunoprecipitation, and GST pull-down. CDO1 function was assessed by proliferation, apoptosis, and migration assays in gain- and loss-of-function models. In vivo tumorigenesis and CDO1-dependent decitabine efficacy were evaluated by subcutaneous xenografts. Patient-derived organoids were used to assess decitabine sensitivity and 5-FU synergy.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Compared with normal controls, CDO1 expression was notably decreased in GC tissues, and its low expression was strongly linked to unfavourable prognosis, supporting its utility as a biomarker for prognosis. Elevated CDO1 levels correlated with an immune-active tumour microenvironment and reduced metastatic signatures. Mechanistically, CDO1 directly bound to PI3K p85α, disrupting p85α-p110α dimerization, thereby attenuating PI3K/AKT phosphorylation and downregulating THBS1 expression. CDO1 overexpression led to reduced proliferation, invasiveness, and EMT, accompanied by increased apoptosis. These effects were reversed by PI3K activation or THBS1 co-overexpression. Decitabine was identified as an agent that epigenetically restores CDO1 expression. Critically, CDO1 knockdown significantly attenuated the anti-tumour efficacy of decitabine in vivo, confirming that decitabine acts primarily through CDO1 reactivation. Decitabine synergized with 5-FU in both organoids and xenografts.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Our data identify CDO1 as both a biomarker for prognosis and a tumour suppressor in gastric cancer. They reveal a CDO1–PI3K/AKT–THBS1 signalling axis and support the epigenetic reactivation of CDO1 by decitabine as a translatable therapeutic strategy.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key po","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13527532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863680","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":"Venetoclax for elderly patients with acute myeloid leukaemia unfit for intensive chemotherapy: Prospects, resistance mechanisms and management strategies","authors":"Jinlin Zhang,&nbsp;Jile Liu,&nbsp;Mohan Zhao,&nbsp;Xiaoyu Zhang,&nbsp;Linlin Liu,&nbsp;Mengnan Li,&nbsp;Changze Cao,&nbsp;Rui Zhang,&nbsp;Mingfeng Zhao","doi":"10.1002/ctm2.70797","DOIUrl":"10.1002/ctm2.70797","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>To date, the treatment of acute myeloid leukaemia (AML) remains a major challenge in hematologic malignancies, particularly among elderly patients who are unfit for intensive chemotherapy. Venetoclax, a BCL-2 inhibitor, in combination with azacitidine, has significantly improved the prognosis and survival of this patient population. However, approximately 30% of patients do not respond to venetoclax-based combination regimens, and most initial responders eventually experience relapse. Therefore, resistance to venetoclax has become a critical bottleneck limiting its long-term clinical benefits. A thorough understanding of the underlying resistance mechanisms and the development of novel strategies to overcome resistance are central to improving survival outcomes in elderly AML patients. The resistance mechanisms of venetoclax are complex and multifaceted, including genetic drivers such as TP53 mutations, FLT3-ITD, and NRAS/KRAS mutations, as well as the upregulation of anti-apoptotic proteins (e.g., MCL-1, BCL-xL), metabolic reprogramming, and altered cellular differentiation states. In response to these factors, emerging therapeutic strategies are rapidly evolving toward precision-based and combination approaches, including combinations with targeted agents (e.g., IDH2 inhibitors, FLT3 inhibitors), MCL-1 inhibitors, optimization of current dosing regimens (e.g., DEC3-VEN), and the development of novel modalities (e.g., antibody-drug conjugates, CAR-T cell therapy). Focusing on the disease characteristics of elderly AML, this narrative review summarizes the clinical efficacy of venetoclax, critically examines the multifaceted mechanisms of venetoclax resistance, and discusses current and emerging therapeutic strategies to overcome this resistance. The goal is to inform clinical practice and guide future translational research.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>This review elucidates the current mechanism of action, therapeutic effects, and limitations of venetoclax, focusing on its use and combination regimens in the specific patient population of elderly individuals with AML who are not suitable for intensive therapy, as well as strategies to overcome resistance, and provides future perspectives for addressing venetoclax resistance.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70797","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148839382","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":"Multi-omics analysis reveals insights into the differentiation between radiological subtypes of early lung adenocarcinoma","authors":"Huiwen Miao,&nbsp;Ruiying Kong,&nbsp;Xiaobo Xu,&nbsp;Mimi Wang,&nbsp;Xiao Teng,&nbsp;Dingli Zhu,&nbsp;Wenyi Zhao,&nbsp;Sheng Cai,&nbsp;Jingqi Zhou,&nbsp;Xiayi Lv,&nbsp;Zhan Zhou","doi":"10.1002/ctm2.70800","DOIUrl":"10.1002/ctm2.70800","url":null,"abstract":"&lt;p&gt;Dear Editor,&lt;/p&gt;&lt;p&gt;Lung adenocarcinoma (LUAD) presenting as ground-glass opacity (GGO) generally has a more favourable prognosis, often exhibiting indolent growth, whereas purely solid lesions are frequently associated with poorer clinical outcomes.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Despite the disparity in clinical trajectories, the underlying molecular drivers dictating this divergence remain poorly understood. This can lead to controversies regarding appropriate surgical methods and potential overtreatment.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Prior studies have identified transcriptome differences between GGO-associated and solid LUAD, but the proteomic and metabolomic landscapes remain insufficiently characterised.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; A comprehensive molecular characterisation of these distinct radiological phenotypes is therefore needed to identify biomarkers associated with tumour aggressiveness and clinical behaviour. To address this gap, we established a prospective cohort of 50 treatment-naïve patients with stage T&lt;sub&gt;1&lt;/sub&gt;N&lt;sub&gt;0&lt;/sub&gt;M&lt;sub&gt;0&lt;/sub&gt; LUAD, including 26 GGO-associated and 24 purely solid tumours, with partially paired adjacent normal tissues. Integrative profiling of the transcriptome, 4D-DIA proteome and untargeted metabolome enabled us to construct a cross-omics molecular atlas delineating the biological differences between these early-stage LUAD subtypes (Figure 1 and Table S1).&lt;/p&gt;&lt;p&gt;Proteomic profiling revealed a profound molecular divergence between the two radiological phenotypes, identifying an extracellular matrix (ECM)-centric signature uniquely enriched in purely solid tumours. Specifically, 267 differentially expressed proteins (DEPs) distinguished the two subtypes, with a striking upregulation (&lt;i&gt;t&lt;/i&gt;-test &lt;i&gt;p&lt;/i&gt; &lt; 0.05 and |log&lt;sub&gt;2&lt;/sub&gt;FoldChange| &gt; 1) of pro-invasive and tissue-remodelling factors such as SPP1, MMP12 and THBS1 in solid lesions (Figure 2A–C and Figure S1). Beyond mere differential expression, protein-protein interaction networks and WGCNA module analyses mapped a subtype-related highly interconnected ECM-associated functional hub. Within this interactome, THBS1 and SPP1 emerged as prominent components of the ECM-associated proteomic signature enriched in solid LUAD (Figure 2D–J and Figures S2–S5). Biologically, these glycoproteins have been implicated in integrin signalling, focal adhesion, and ECM remodelling, processes closely associated with tumour invasion and progression.&lt;span&gt;&lt;sup&gt;5, 6&lt;/sup&gt;&lt;/span&gt; Consistent with their robust roles in driving malignancy, our clinical validation using the TCGA-LUAD external cohort revealed that high expression of THBS1 (&lt;i&gt;p&lt;/i&gt; = 0.0108, hazard ration [HR] = 1.54, 95% confidence interval [95% CI]: 1.06–1.90) and SPP1 (&lt;i&gt;p&lt;/i&gt; = 0.0190, HR = 1.42, 95% CI: 1.10–2.14) significantly correlates with shortened overall survival. These findings support the prognostic relevance of ECM-associated markers identified in our proteomic analysis.&lt;/p&gt;&lt;p&gt;The cl","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70800","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148839423","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":"Pattools‑implemented methylation vector analysis reveals aberrant subtype‑specific methylation in lung cancer across tissue and plasma cfDNA","authors":"Zehua Dong,&nbsp;Yifeng Luo,&nbsp;Tingting Hu,&nbsp;Yihang Cheng,&nbsp;Qiaoling Ren,&nbsp;Li Xu,&nbsp;Yuan Tan,&nbsp;Wei Li,&nbsp;Yaoxiang Sun,&nbsp;Mingzhi Chen,&nbsp;Zhonghua Shen,&nbsp;Bin Zhang,&nbsp;Youhuang Bai,&nbsp;Yue Tao,&nbsp;Zhihong Cao,&nbsp;Deqiang Sun","doi":"10.1002/ctm2.70812","DOIUrl":"10.1002/ctm2.70812","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Lung cancer is characterised by high mortality and encompasses various subtypes with markedly different treatment outcomes. While individual subtypes have been studied, comprehensive genome-wide and fine-scale DNA methylation analyses across subtypes remain unexplored. This study aims to identify true subtype-specific aberrant methylation by developing a novel method that eliminates cell-origin and immune confounding, moving beyond traditional approaches.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We assembled an in-house cohort of 115 tissue samples across five groups (CTL, LUAD, LUSC, LCC, SCLC) with detailed clinicopathological annotations. Matched plasma cfDNA samples (<i>n</i> = 24; 9 LUAD, 7 LUSC, 8 healthy) were collected for translational assessment. We developed an MV analysis method implemented in the open-source toolkit pattools to differentiate cell-specific fragments in bulk BS-seq data and identify subtype-specific methylation vector regions (SMVRs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Genome-wide methylation profiling revealed that subtype-specific signals originate from distinct cell types—alveolar epithelium in LUAD, head and neck epithelium in LUSC, fibroblasts in LCC, and endocrine cells in SCLC—with additional immune infiltration influences. Using pattools-based MV analysis, we identified 500 key SMVRs per subtype. In matched plasma cfDNA, these tissue-derived SMVRs demonstrated promising discriminatory power for LUAD (AUC = 0.98, 95% CI: 0.95 to 1.00) and LUSC (AUC = 0.88, 95% CI: 0.79 to 0.97) in binary classification, and AUCs of 0.95 (95% CI: 0.90 to 1.00), 0.75 (95% CI: 0.62 to 0.88), and 0.63 (95% CI: 0.48 to 0.78) for LUAD, LUSC and healthy samples, respectively, in multi-class classification.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The MV analysis in pattools effectively uncovers subtype-specific aberrant methylation signals, offering potential for precise diagnosis and subtyping in tissue and liquid biopsy. Independent validation in larger cohorts is required before clinical translation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70812","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148839392","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 the cytosine base editing barrier: Virus-like particles with uracil-DNA glycosylase inhibition unlocking the clinical potential","authors":"Yuqing Wu,&nbsp;Xingyu Zhu,&nbsp;Junjie Zhu,&nbsp;Jia Chen,&nbsp;Jiaxu Hong","doi":"10.1002/ctm2.70803","DOIUrl":"10.1002/ctm2.70803","url":null,"abstract":"&lt;p&gt;The vast majority of known genetic pathogenic variants are driven by single base substitutions, particularly A-to-G and C-to-T transitions (or their respective complementary T-to-C and G-to-A mutations).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Cytosine base editors (CBEs) and adenine base editors (ABEs) can precisely correct these errors without introducing DNA double-strand breaks.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; However, the clinical translation of in vivo base editing has consistently been constrained by delivery hurdles. Although adeno-associated viruses (AAVs) are widely used, their prolonged gene expression introduces safety risks, including more severe off-target editing and the potential for genomic integration.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Lipid nanoparticles (LNPs) offer a transient alternative, yet their efficacy is primarily restricted to the liver.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Virus-like particles (VLPs) represent a highly promising delivery modality, capable of transiently delivering genome editors as ribonucleoproteins (RNPs).&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Moreover, their tissue tropism can be modulated by engineering the envelope glycoproteins, enabling targeted delivery to different tissues, organs, and even specific cell types. While previous studies have successfully established VLP-mediated in vivo delivery for Cas9 nuclease, ABEs and prime editors, VLP-mediated CBE delivery had thus far only been demonstrated in vitro.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; It remained unclear whether VLPs could achieve meaningful in vivo cytosine base editing.&lt;/p&gt;&lt;p&gt;To address this unmet clinical need, the current study pinpointed the underlying biological barrier: host endogenous UNGs actively excise the edited uracils.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Conventional VLPs deliver a finite, rapidly degrading supply of uracil DNA glycosylase inhibitor (UGI) proteins. Consequently, host DNA repair mechanisms suppress the editing outcomes. By engineering the transformer base editor (tBE) and further optimising the Moloney murine leukaemia virus (MMLV)-derived VLP system to generate tBE-VLP4, this strategy successfully enhanced the recruitment and packaging of UGI proteins. This translates into a transient yet robust in vivo editing platform. By overcoming innate repair defences, it ensures stable therapeutic effects.&lt;/p&gt;&lt;p&gt;The rapid onset of action highlights the clinical potential of this system. In a mouse model of tyrosinemia type I, tBE-VLP4 targeting &lt;i&gt;mHpd&lt;/i&gt; achieved up to 64.2% editing efficiency in the liver, successfully rescuing the lethal disease phenotype. Notably, treated mice could be safely withdrawn from the protective drug nitisinone (NTBC) just two days post-VLP injection. For managing clinical metabolic crises, this extremely rapid therapeutic onset demonstrates a distinct advantage over AAV-mediated therapies, which typically require weeks of bridging therapy due to lagging expression kinetics. Furthermore, tBE-VLP4 successfully lowered serum cholesterol by efficiently disrupt","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70803","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148839462","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}