Clinical and Translational Medicine最新文献

{"title":"Photopharmacology: A new paradigm for vision restoration","authors":"Robert J. Casson","doi":"10.1002/ctm2.70779","DOIUrl":"10.1002/ctm2.70779","url":null,"abstract":"<p>Inherited retinal diseases (IRDs) comprise a diverse group of genetic disorders characterized by progressive degeneration of photoreceptors, ultimately leading to irreversible vision loss and blindness. Among IRDs, retinitis pigmentosa (RP) is one of the most common causes of blindness in the working-age population in high-income countries, with an estimated prevalence of approximately 1 in 3000–4000 individuals.<span><sup>1-3</sup></span> The approval of voretigene neparvovec (Luxturna) for RPE65-associated retinal dystrophy established a landmark proof-of-principle for gene replacement therapy in IRD. However, current gene therapy strategies generally remain mutation-specific and require sufficient survival of functional photoreceptors. As degeneration progresses and photoreceptors are lost, the therapeutic challenge shifts from preserving vision to restoring it. This unmet need has driven the development of gene-agnostic restorative strategies that seek to bypass or replace the damaged outer retina, including electronic retinal prostheses, optogenetic therapies, cell-based approaches and, more recently, chemical photoswitches.<span><sup>4</sup></span></p><p>Chemical photoswitches represent a distinctive pharmacological approach to vision restoration. These light-responsive small molecules reversibly modulate neuronal ion channels, enabling surviving inner retinal neurons to respond to light and engage downstream visual pathways.<span><sup>5</sup></span> Evidence from preclinical studies suggests that KIO-301 selectively associates with hyperpolarization-activated cyclic nucleotide-gated channels expressed by retinal ganglion cells.<span><sup>6</sup></span> Light-induced conformational changes in the molecule modulate channel activity, conferring light responsiveness to a subclass of retinal ganglion cells.<span><sup>6</sup></span> In effect, these retinal ganglion cells function as surrogate photoreceptors, transmitting light-evoked signals through the optic nerve to higher visual centres and thereby providing the neural substrate for visual perception. The proposed mechanism of action is shown in Figure 1. Unlike prosthetic, gene-based or cell-based interventions, photopharmacology does not require implanted hardware, gene transfer or cellular replacement. Instead, it exploits surviving inner retinal circuitry through intravitreal administration of a small molecule, offering the potential for mutation-agnostic treatment, repeat dosing and iterative optimisation through medicinal chemistry. These features also confer several practical advantages over existing restorative approaches. As a small-molecule therapy, photoswitches can be manufactured using established pharmaceutical processes, administered using routine intravitreal injection techniques familiar to ophthalmologists and refined through successive generations of medicinal chemistry. This pharmacological flexibility provides opportunities to optimise potency, spectral sensitivity, d","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70779","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148722077","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":"TALDO1 promotes lipid metabolic reprogramming and immunosuppressive microenvironment remodelling in hepatocellular carcinoma","authors":"Fenglin Lv, Huaxin Zhou, Jingyan Yang, Jianglei Xu, Fanqing Bi, Yi Zhou, Hao Zhang, Qian Ye, Lin Gao, Bin Jin","doi":"10.1002/ctm2.70771","DOIUrl":"10.1002/ctm2.70771","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Hepatocellular carcinoma (HCC) is characterized by pronounced metabolic reprogramming and is frequently accompanied by the development of an immunosuppressive microenvironment. However, the key molecular mediators linking tumour metabolic dysregulation to immune microenvironment remodelling remain insufficiently defined. This study aimed to identify critical metabolic genes in HCC and to investigate their roles in lipid metabolic reprogramming and immunosuppression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A deep autoencoder was used to extract latent metabolic features from HCC and identify TALDO1 as a key candidate gene. The expression pattern and prognostic significance of TALDO1 were evaluated across multiple independent cohorts and further validated in clinical specimens. Multi-omics analyses combined with experimental validation were then used to elucidate the role of TALDO1 in lipid metabolic reprogramming and its effects on immune microenvironment remodelling in HCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>TALDO1 was identified as a key metabolic gene associated with HCC progression and was consistently upregulated across multiple clinical cohorts. Mechanistically, TALDO1 promoted lipogenesis and lipid accumulation in HCC cells by suppressing AMPK activation and sustaining SREBP1 maturation. TALDO1 silencing also reduced the secretion of several fatty acids and lipid mediators. Multi-omics analyses together with multiplex immunofluorescence validation showed that high TALDO1 expression was associated with an immunosuppressive microenvironment in HCC. Coculture experiments further demonstrated that TALDO1 silencing attenuated the ability of HCC cells to induce M2-like macrophage polarization and promote phenotypes associated with T-cell exhaustion. In vivo, TALDO1 loss was accompanied by reduced immunosuppressive cell infiltration, enhanced effector T-cell activity, and impaired tumour growth. Consistently, TALDO1 silencing also markedly suppressed tumour growth in patient-derived xenograft models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>TALDO1 promotes lipid metabolic reprogramming in HCC and participates in the formation of an immunosuppressive microenvironment. These findings suggest that TALDO1 may serve as a key molecule linking metabolic abnormalities to immune microenvironment remodelling and may have potential therapeutic significance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70771","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705386","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":"Integrin α5β1 in pancreatic ductal adenocarcinoma: Tumour‒stroma crosstalk, hypoxia and therapeutic targeting","authors":"Chenzhe Ma,&nbsp;Yingying Wang,&nbsp;Yumin Li","doi":"10.1002/ctm2.70759","DOIUrl":"10.1002/ctm2.70759","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and is characterised by aggressive biological behaviour, marked therapeutic resistance and a dense desmoplastic tumour microenvironment. Integrin α5β1, the principal fibronectin receptor, has emerged as an important mediator of tumour-stroma interactions through its roles in cell adhesion, mechanotransduction, migration, survival and extracellular matrix (ECM) remodelling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Main body</h3>\u0000 \u0000 <p>Increasing evidence indicates that integrin alpha 5 (ITGA5)/integrin α5β1 is upregulated in PDAC cells and stromal compartments and is associated with invasion, fibrosis, therapeutic resistance and poor prognosis. Hypoxia, a defining feature of PDAC, may further enhance α5β1-related signalling by promoting stromal activation and ECM remodelling. This review summarises the structural and signalling features of integrin α5β1, its role in hypoxia-related interactions between tumour cells and the stroma, its contribution to therapeutic resistance in PDAC, and current therapeutic strategies targeting this integrin.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Integrin α5β1 is a biologically relevant therapeutic target for modulating the fibrotic stroma and overcoming treatment resistance in PDAC, and it may also be implicated in tumorstroma crosstalk within the hypoxic microenvironment. Successful clinical translation of α5β1-targeted strategies will likely require further mechanistic investigation, biomarker-guided patient selection, and rational combination approaches to address pathway redundancy and the limited efficacy of monotherapy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13455686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148701000","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":"Endogenous CD155 drives metabolic reprogramming via PI3K/AKT/HIF-1α-glycolysis axis to mediate anti-PD-1 resistance in non-small cell lung cancer","authors":"Wei-Guang Du,&nbsp;Xi-Yang Tang,&nbsp;Yu-Long Zhou,&nbsp;Run-Ze Zhang,&nbsp;Zhi-Bo Feng,&nbsp;Meng-Chao Li,&nbsp;Jun-Yang Pan,&nbsp;Yao Lv,&nbsp;Xiao-Liang Xu,&nbsp;Xiao-Long Yan,&nbsp;Nan Ma,&nbsp;Jin-Bo Zhao","doi":"10.1002/ctm2.70741","DOIUrl":"10.1002/ctm2.70741","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Objective&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Anti-PD-1 therapy resistance remains a critical barrier in non-small cell lung cancer (NSCLC) management, and the underlying mechanisms are incompletely defined.&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;We generated CD155‑knockout (KO) NSCLC cell lines using the CRISPR‑Cas9 system and performed systematic multi‑omics analyses, including single‑cell RNA‑seq, bulk RNA‑seq, proteomics, and metabolomics. The key molecular mechanisms were further validated by immunohistochemistry (IHC), western blotting, and chromatin immunoprecipitation (ChIP). Functional assays assessed cell proliferation, migration, and metabolic phenotypes, while the therapeutic efficacy was assessed in vivo using AAV9_shCD155.&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;Single-cell sequencing revealed aberrantly high CD155 expression in NSCLC patients with poor response to anti-PD-1 therapy. High CD155 expression in NSCLC tissues correlated with unfavourable prognosis. ETS1 was identified as a direct transcriptional driver of CD155. Multi-omics analysis and functional assays demonstrated that CD155 upregulates the expression of key glycolytic proteins (GLUT1, GLUT3, LDHB) by activating the PI3K/AKT/HIF-1α signalling axis, thereby driving glycolytic metabolism, proliferation, and migration of tumour cells. CD155 knockout significantly suppressed these malignant phenotypes. In xenograft mouse models, monotherapy with AAV9_shCD155 effectively inhibited tumour growth and postoperative recurrence. More importantly, in humanised mouse models, combining AAV9_shCD155 with pembrolizumab produced synergistic anti-tumour effects, more significantly suppressing tumour growth and promoting immune cell infiltration into the tumour microenvironment.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;CD155 mediates anti-PD-1 resistance by activating PI3K/AKT/HIF-1α-driven glycolytic reprogramming. Targeting CD155 combined with anti-PD-1 overcomes resistance, supporting a dual-target therapeutic strategy.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;CD155 is identified as a key driver of anti-PD-1 resistance in NSCLC.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;CD155 promotes tumour glycolysis and malignant progression via the PI3K/AKT/HIF-1α signalling axis.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;AAV9_shCD155 combined with anti-PD-1 markedly inhibits tumour ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70741","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148705427","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":"SLC7A5 promotes colorectal cancer liver metastasis by reprogramming tryptophan metabolism through the Kyn/XANA‒AhR axis and reshaping the immune microenvironment","authors":"Yaohao Luo,&nbsp;Lei Li,&nbsp;Shanbao Li,&nbsp;Xinshuai Wang,&nbsp;Zeping He,&nbsp;Fangbin Song,&nbsp;Jun Qin,&nbsp;Jinyan Zhang,&nbsp;Junming Xu","doi":"10.1002/ctm2.70766","DOIUrl":"10.1002/ctm2.70766","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Colorectal cancer (CRC) is a leading cause of cancer-related death and is associated with high recurrence rates. Solute carrier family 7 member 5 (SLC7A5), a core transporter that facilitates the transmembrane movement of tryptophan, plays a role in various cancers. However, whether and how SLC7A5 promotes colorectal liver metastasis (CRLM) through tryptophan metabolism reprogramming and immune remodelling remain unexplored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We integrated public datasets and clinical specimens to analyse SLC7A5 expression and prognosis, and validated its role in proliferation and metastasis using in vitro assays and in vivo models. Targeted metabolomics and isotope tracing identified kynurenine (Kyn) and xanthurenic acid (XANA) as downstream metabolites of SLC7A5. Single-cell RNA sequencing (scRNA-seq) and conditioned medium experiments were used to assess the impact of SLC7A5 on the tumour immune microenvironment (TIME).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>SLC7A5 expression increases sequentially in normal tissue, primary tumours and liver metastases, and higher SLC7A5 levels are associated with worse prognosis. SLC7A5 facilitates CRC cell growth, metastasis and epithelial‒mesenchymal transition (EMT) by promoting the production of Kyn and XANA and subsequent activation of the aryl hydrocarbon receptor (AhR). scRNA-seq analysis and conditioned medium experiments demonstrated that SLC7A5 knockdown reprograms the TIME by driving macrophages towards an antigen-presenting phenotype, alleviating CD8⁺ T-cell exhaustion, polarising CD4⁺ T cells towards Th1/Th17 subsets and triggering antigen-driven immunoglobulin G (IgG)-secreting B-cell clonal expansion, effects that were reversed by exogenous Kyn/XANA supplementation. Moreover, combination therapy with the SLC7A5 inhibitor JPH203 and anti-programmed cell death protein 1 (PD-1) antibody produced synergistic tumour growth inhibition and heightened antitumour immune responses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Collectively, our findings reveal that SLC7A5 drives CRLM through tryptophan/Kyn/XANA–AhR signalling and concomitant remodelling of the TIME, positioning SLC7A5 as a promising target for combination therapy with anti-PD-1 in CRLM.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13448136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683438","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":"Chemokine receptor CCR1 restrains adipose tissue remodelling via cAMP/PKA/CREB signalling and adipocyte‒macrophage crosstalk in mice","authors":"Suili Cai,&nbsp;Mengchen Ma,&nbsp;Yuqin Zhu,&nbsp;Mengru Shi,&nbsp;Xiaoyan Dai,&nbsp;Yujie Wang,&nbsp;Mengru Li,&nbsp;Yanwen Yu,&nbsp;Yajiao Wang,&nbsp;Liang Xu","doi":"10.1002/ctm2.70762","DOIUrl":"10.1002/ctm2.70762","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;Adipose tissue remodelling, encompassing white adipose tissue (WAT) browning alongside brown adipose tissue (BAT) activation, holds promise for combating obesity, yet the endogenous chemokine receptors that restrain this plasticity remain ill-defined. Here, we uncover that C‒C chemokine receptor 1 (CCR1) restrains adipocyte remodelling and energy expenditure.&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;A high-fat diet (HFD) was provided to systemic and adipocyte-specific &lt;i&gt;Ccr1&lt;/i&gt; knockout mice. The CCR1-selective antagonist BX471 was administered to HFD-fed wild-type (WT) mice as a preventive regimen. Energy expenditure was assessed via indirect calorimetry; BAT thermogenic activity and WAT beiging were quantified through histology and gene expressin analyses. Adipose tissue macrophage homeostasis was analysed via flow cytometry. Peritoneal macrophages were differentiated into either the M1 or M2 state, and conditioned media were applied to the adipocytes.&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;In HFD-fed mice, &lt;i&gt;Ccr1&lt;/i&gt; ablation conferred resistance to obesity and insulin resistance, coupled with enhanced WAT browning, augmented BAT thermogenesis and elevated energy expenditure. These metabolic benefits were associated with a shift towards M2 macrophage polarisation and reduced adipose tissue inflammation. Adipocyte-specific &lt;i&gt;Ccr1&lt;/i&gt; knockout recapitulated these phenotypes. BX471 administration in WT mice phenocopied the metabolic effects of &lt;i&gt;Ccr1&lt;/i&gt; deficiency under HFD conditions. Mechanistically, in vitro experiments suggested that &lt;i&gt;Ccr1&lt;/i&gt; loss suppressed Gαi-dependent signalling, leading to increased intracellular cyclic adenosine monophosphate (cAMP) and subsequent protein kinase A/cAMP-response element-binding protein 1 (PKA/CREB) activation, thereby promoting thermogenic gene expression in adipocytes. In addition, conditioned media from M2-polarised macrophages enhanced thermogenic gene expression in adipocytes, and this effect was further potentiated in &lt;i&gt;Ccr1&lt;/i&gt;-deficient adipocytes.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;CCR1 regulates adipose tissue remodelling and systemic energy expenditure, at least in part, through cAMP/PKA/CREB signalling and macrophage homeostasis. Pharmacological inhibition of CCR1 attenuates obesity development, suggesting a potential preventive strategy.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13444349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676577","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":"The evolving landscape of the Warburg effect in gastric cancer: From molecular mechanisms to targeted therapy","authors":"Guanmo Liu,&nbsp;Pan Li,&nbsp;Zizhuo Li,&nbsp;Jie Li,&nbsp;Chenggang Zhang,&nbsp;Yihua Wang,&nbsp;Weiming Kang,&nbsp;Xin Ye","doi":"10.1002/ctm2.70772","DOIUrl":"10.1002/ctm2.70772","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;Gastric cancer (GC) remains a major health burden because of late-stage diagnosis and resistance to systemic therapy.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Main body&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;In GC, the Warburg effect is driven by interconnected hypoxia and oncogenic signalling, non-coding RNA networks and transcriptional and epigenetic rewiring. These regulators converge on glucose transport and core glycolytic enzymes, including HK2, PFKFB3, PKM2 and LDHA. The resulting increase in aerobic glycolysis, pyruvate-to-lactate conversion and lactate export supports biosynthesis, redox homeostasis and survival under metabolic stress. Beyond its bioenergetic role, lactate acts as a signalling metabolite that acidifies and remodels the tumour microenvironment. It impairs CD8-positive T and natural killer cells function, promotes regulatory T cells accumulation and M2 macrophages polarisation, activates stromal cells and facilitates epithelial–mesenchymal transition and immune evasion. Together, tumour-intrinsic metabolic adaptation and lactate-mediated microenvironmental reprogramming contribute to resistance to chemotherapy, targeted therapy and immunotherapy. Translationally, metabolic imaging, circulating LDH and lactate-related markers, exosomal glycolytic enzymes, gene-expression signatures and lactylation-related features may improve prognostic assessment, treatmentresponse prediction and patient stratification. These findings support biomarker-guided combination strategies that target tumour metabolism, lactate production or transport and stromalimmune crosstalk alongside standard therapies. This review uniquely integrates direct GC-derived evidence with indirect evidence from non-GC models and clinical trials and grades biomarkers and metabolic interventions according to their translational maturity.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Overall, the Warburg effect represents both a central driver of GC progression and a clinically relevant metabolic vulnerability.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Key points&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;The Warburg effect in gastric cancer is a multi-module metabolic state, not a single glycolytic phenotype.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Lactate links glycolytic reprogramming to stromal activation, immune evasion and therapy resistance.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Microbiota, especially &lt;i&gt;H. pylori&lt;/i&gt;, modulates glycolysis and creates actionable upstream vulnerabilities.&lt;/li&gt;\u0000 ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13443148/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676728","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":"SelO-mediated nicotinamide adenine dinucleotide hydrolysis and its implications for metabolic therapies","authors":"Teng Zhang,&nbsp;Ting Wang,&nbsp;Yuan Fu","doi":"10.1002/ctm2.70773","DOIUrl":"10.1002/ctm2.70773","url":null,"abstract":"&lt;p&gt;Nicotinamide adenine dinucleotide (NAD) exists in two distinct cellular forms: the oxidised state NAD+ and the reduced state NADH. Acting as a dynamic redox intermediary within cellular energy production, this molecule drives essential pathways, including the tricarboxylic acid (TCA) cycle for pyruvate metabolism (derived from glycolysis) and β-oxidation for lipid catabolism. Essentially, NAD+ accepts two electrons and one proton from carbohydrates and lipids, the primary energy substrates for mammalian cells, to become the high-energy carrier NADH. NADH subsequently fuels oxidative phosphorylation to generate ATP. Consequently, the NAD+/NADH ratio acts as a master regulator of nearly all metabolic and oxidoreductive processes, including glycolysis and fatty acid oxidation.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;However, the regulation of NAD extends beyond toggling between NAD+ and NADH. The absolute size of the overall NAD pool is a critical and independent variable. Historically, much of the research has relied solely on measuring the NAD+/NADH ratio, operating under the assumption that fluctuations in this parameter adequately reflect the availability of these molecules for metabolic reactions. In reality, mammalian cells actively acquire NAD through biosynthesis from precursors like nicotinamide and consume it via enzymes such as PARPs and sirtuins (SIRTs) during post-translational protein modifications.&lt;span&gt;&lt;sup&gt;1, 3&lt;/sup&gt;&lt;/span&gt; Conceivably, the absolute size of the NAD pool should also dictate its molecular availability. Furthermore, NAD pools are highly compartmentalised within the cell. The extracellular, cytosolic, and mitochondrial spaces represent three relatively independent NAD pools. Specifically, the shuttling of NAD between the cytosol and mitochondria does not simply occur via passive diffusion, but requires the dedicated transporter SLC25A51.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Although the biosynthesis of NAD is well characterised in both the mitochondrial matrix and the cytosol, how NAD levels are proactively controlled through degradation within the mitochondria remains poorly understood. We recently identified that the mitochondrial matrix protein SELENOO (SelO), a selenocysteine-containing protein, catalyses the hydrolysis of NAD into nicotinamide mononucleotide (NMN) and AMP.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Interestingly, this enzyme was originally characterised as mediating AMPylation, a rare post-translational modification that transfers an AMP moiety from ATP to serine, threonine, or tyrosine residues on target proteins.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; While both enzymatic functions share the same adenosine-binding pocket, they differ in their reliance on the C-terminal selenocysteine. Specifically, this rare residue is absolutely critical for SelO's NAD hydrolysis activity but remains dispensable for its AMPylation function. Physiologically, cells may harbour both the full-length, selenocysteine-containing isoform and a truncated isofor","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13443136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676744","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":"Integrating pathological morphologies and molecular profiles for clinical biomarker discovery with unified multimodal embedding","authors":"Chaofei Gao,&nbsp;Qian Zhang,&nbsp;Peng Zhang,&nbsp;Shao Li","doi":"10.1002/ctm2.70765","DOIUrl":"10.1002/ctm2.70765","url":null,"abstract":"&lt;p&gt;Spatial omics technologies have revolutionised our understanding of tissue architecture, revealing novel molecular biomarkers for clinical diagnosis and disease management.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Despite these advances, the clinical deployment of spatial omics remains limited by high sequencing costs and complex experimental workflows.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Moreover, biomarkers discovered in this manner are typically validated only in small cohorts, lacking the generalizability required for broader clinical populations.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; By contrast, cost-effective and widely available haematoxylin and eosin (H&amp;E)-stained pathology slides have remained the gold standard in oncology for decades.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; However, H&amp;E slides capture only morphologies, lacking the detailed molecular information. Thus, integrative analysis of pathological morphologies and molecular profiles holds the key to translating spatial biology into precision oncology, enabling the discovery of generalizable biomarkers for clinical application.&lt;/p&gt;&lt;p&gt;However, current multimodal methods integrating morphologies and molecular profiles typically fall into a dilemma between interpretability and generalizability.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; On one hand, top-down approaches start from clinical phenotypes and employ fully supervised models to predict outcomes, achieving high accuracy but offering limited biological interpretability.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; On the other hand, bottom-up approaches start from defined molecular mechanisms to identify biomarkers anchored to specific biological processes, yet these biomarkers often exhibit poor cross-cohort generalizability, hindering their clinical applications.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Bridging this gap requires a multimodal framework that accurately characterises clinical outcomes while revealing the cross-modal associations that underpin them. Here, we introduce Multi-Embed,&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; a recently published self-supervised framework enabling synchronous cross-modal inference and integration of multilevel pathological morphologies and multilayer molecular profiles with unified embedding. Based on these capabilities, Multi-Embed enables clinical biomarker discovery with both generalizability and interpretability across multiple scenarios, offering a practical route to bridge biological discovery with clinical practice.&lt;/p&gt;&lt;p&gt;Multi-Embed is established upon the principle of cross-modality network modular association, which was identified through systematic analysis of multi-level data spanning traditional Chinese and Western medicine (Figure 1). It establishes a unified embedding space that bridges macroscopic morphologies and microscopic molecular profiles, enabling cross-modality inference and integration.&lt;/p&gt;&lt;p&gt;The advantages of Multi-Embed lie in its capacity for both deeper mechanistic insight and broader biological coverage. In terms of depth, it achieves state-of-the-art perfo","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13439214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148673175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Efficacy and safety of disitamab vedotin (RC48) combined with camrelizumab and S-1 for neoadjuvant therapy of locally advanced gastric cancer with HER2-overexpressing: Preliminary results of a prospective, single-arm, phase II study”","authors":"","doi":"10.1002/ctm2.70775","DOIUrl":"10.1002/ctm2.70775","url":null,"abstract":"<p>We apologise for these errors.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 8","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13443131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148676591","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}