Clinical and Translational Medicine最新文献

{"title":"Exploratory single-nucleus multiomics analysis of myeloid cell states associated with neoadjuvant chemotherapy response in pancreatic ductal adenocarcinoma.","authors":"Mercy Ojetunde, Li Ma, Hillary G Goodney, Alyson M Stevens, Alan Mizener, Emidio E Pistilli, Sascha Ott, Kawther Abdilleh, Barbara Szomolay, Gangqing Hu, Timothy D Eubank, Brian A Boone","doi":"10.1002/ctm2.70810","DOIUrl":"10.1002/ctm2.70810","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) continues to be one of the most lethal human malignancies, with the vast majority of patients ineligible for immunotherapy. Tumour-associated macrophages (TAMs) are key regulators of the PDAC tumour microenvironment (TME), yet their transcriptional and epigenomic heterogeneity in the context of chemotherapy response is poorly understood. Therefore, we performed an exploratory single nucleus multiomics analysis of PDAC tumors stratified by histopathologic response to neoadjuvant chemotherapy.</p><p><strong>Methods: </strong>Surgical resection specimens from PDAC patients were classified as responders or non-responders using the American College of Pathologists (CAP) histopathologic criteria. Frozen tissue underwent simultaneous snRNA-seq and snATAC-seq on the 10x Genomics Chromium Single Cell Multiome platform, followed by downstream analyses such as differential gene expression, GO and hallmark pathway enrichment, pseudotime trajectory inference and ChromVAR transcription factor motif analysis.</p><p><strong>Results: </strong>Multiomics profiling of 30 840 high-quality nuclei revealed a myeloid compartment that differed in composition and transcriptional state between CAP-defined responders and non-responders in this small cohort. We observed a trend toward higher LAM-like state proportions in the responders than non-responders (38.4% vs. 26.7%), although this disparity did not achieve statistical significance. The transcriptional programs of the responder myeloid cells are associated with phagocytosis and lipid handling. Chromatin accessibility analysis further suggested candidate response-associated transcription factor motif accessibility patterns.</p><p><strong>Conclusions: </strong>Neoadjuvant-treated PDAC tumours from CAP-defined responders in this cohort myeloid landscape with apparent enrichment of LAM-like states and immune-activating transcriptional/epigenetic programs. However, these findings are preliminary and hypothesis-generating because of the small cohort size, heterogeneous treatment regimens, absence of matched pre-treatment biopsies, and lack of knockout validation. Larger treatment cohorts and functional/mechanistic studies are needed to determine whether LAM-like myeloid programs contribute to chemotherapy response or reflect a consequence of chemotherapy treatment.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":"e70810"},"PeriodicalIF":7.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13574543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148967099","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":"Testicular toll with viral intrusion: Molecular insights into the impact of chronic HIV infection on male fertility.","authors":"Tousif Ahmed Hediyal, Elizabeth M Stone, Omar Shukri, Victoria L Schaal, Amin Foroughi-Nezhad, Murali Devanaboyina, Josef S Crenshaw, Amir Elrefaie, Sree Kolli, Camryn N Davis, Dinesh Pradhan, Sowmya V Yelamanchili, Gurudutt Pendyala","doi":"10.1002/ctm2.70815","DOIUrl":"10.1002/ctm2.70815","url":null,"abstract":"<p><strong>Background: </strong>Human immunodeficiency virus (HIV) infection remains a major global health concern, compromising immune function and increasing susceptibility to opportunistic infections. Over the past two decades, fertility desire among people living with HIV has remained low due to poor health, fear of transmission and restrictive reproductive policies. In men, particularly those in advanced stages of infection, HIV has been associated with profound alterations in semen quality, including reduced ejaculate volume, impaired sperm motility, abnormal morphology and increased incidence of sperm aneuploidy factors that collectively contribute to male infertility.</p><p><strong>Methods: </strong>This study explored the molecular mechanisms of HIV-associated male infertility using a preclinical HIV-1 transgenic (Tg) rat model. Real-time PCR (RT-PCR) and protein expression analyses were performed to evaluate the expression of cation channels of sperm (CatSper 1-4), along with mitochondrial and inflammatory gene networks. Histopathological examination, computer-assisted semen analysis (CASA), nuclear morphology assessment, and transcriptomic sequencing were used to characterize structural, functional, and molecular alterations in the testes and sperm of Tg animals.</p><p><strong>Results: </strong>RT-PCR and protein expression analyses revealed marked downregulation of CatSper1-4 channels, along with dysregulation of mitochondrial and inflammatory gene networks in the testes of Tg animals. Histopathological examination further demonstrated structural disruptions within the seminiferous tubules of Tg rats. Functional assessments using CASA and nuclear morphology analysis confirmed reduced motility and abnormal sperm morphology in Tg rats. Complementary transcriptomic sequencing identified novel gene signatures and disrupted pathways associated with testicular dysfunction in Tg rats.</p><p><strong>Conclusion: </strong>Collectively, our findings demonstrate that HIV-1 transgene expression impairs sperm production and function at both mRNA and protein levels by disrupting ion channel regulation and perturbing broader molecular pathways, ultimately contributing to male infertility. This study provides clinically relevant insights into reproductive complications in HIV-infected individuals and may inform future therapeutic strategies.</p><p><strong>Key points: </strong>HIV-1 transgene expression impairs testicular architecture and spermatogenesis. CatSper 1-4 channels downregulation is associated with impaired sperm function. Mitochondrial dysfunction and altered immune signaling pathways accompany abnormal sperm functions. HIV-1 transgenes induce profound abnormalities in sperm morphology, motility, and widespread transcriptional remodeling of reproductive pathways.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":"e70815"},"PeriodicalIF":7.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929146","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":"Viral protease sensing for programmable antiviral lytic cell death: The path to trials.","authors":"Lin Li, Xiu-Li Yan, Cheng-Feng Qin","doi":"10.1002/ctm2.70842","DOIUrl":"10.1002/ctm2.70842","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":"e70842"},"PeriodicalIF":7.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975890","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":"Synthetic fluorescent proteins: Bridging advanced imaging technologies and clinical practice.","authors":"Zhengda Chen, Xianjun Chen, Yi Yang","doi":"10.1002/ctm2.70828","DOIUrl":"10.1002/ctm2.70828","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":"e70828"},"PeriodicalIF":7.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13570187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148954939","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":"Circulating tumour cells for guiding antibody‒drug conjugate therapy: Role of artificial intelligence.","authors":"Vahid Yaghoubi Naei, Mehran Dabiri, Lihua Chen, Jiajia Li, I-Han Wang, Gungun Lin, Majid Ebrahimi Warkiani","doi":"10.1002/ctm2.70748","DOIUrl":"10.1002/ctm2.70748","url":null,"abstract":"<p><p>Antibody‒drug conjugates (ADCs) represent a major advance in precision oncology, yet their effectiveness depends critically on adequate target antigen expression. Tumour heterogeneity and dynamic antigen expression during treatment pose major challenges for conventional tissue biopsies used in patient selection. Liquid biopsy components such as circulating tumour cells (CTCs) enable real-time, minimally invasive monitoring of tumour burden, molecular characteristics and target antigen status. This review evaluates the potential of CTC analysis to overcome the key challenges in ADC therapy, including real-time target profiling, enhanced patient stratification and longitudinal monitoring of treatment response. While acknowledging that direct clinical evidence for CTC-guided ADC selection remains limited and prospective validation is still needed, we integrate clinical evidence from CTC-guided trials across different cancer types and propose pragmatic decision-making frameworks to incorporate CTC testing into ADC treatment strategies. We also examine how artificial intelligence (AI) has improved CTC detection accuracy and discuss exploratory AI models for multi-omics integration and hypothetical AI-guided ADC recommendation systems, clearly distinguishing these by their current level of clinical evidence. Liquid biopsy-guided ADC selection has the potential to enable more personalised cancer treatment as CTC technologies advance and standardisation improves.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":"e70748"},"PeriodicalIF":7.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612861/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036602","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":"Microglia and neuroinflammation: An in-depth analysis from functional diversity to disease mechanisms.","authors":"Jie Chen, Wangzheqi Zhang, Lizhou Song, Yan Liao, Haoling Zhang, Yiyang Xia, Derong Cui","doi":"10.1002/ctm2.70839","DOIUrl":"10.1002/ctm2.70839","url":null,"abstract":"<p><strong>Background: </strong>Microglia are essential regulators of central nervous system homeostasis and participate in immune surveillance, inflammatory regulation, phagocytosis, metabolic adaptation, and tissue repair. Recent single cell and spatial omics studies have revealed extensive microglial heterogeneity, challenging the traditional M1/M2 classification. However, the functional significance and therapeutic potential of distinct microglial states remain highly context dependent.</p><p><strong>Methods: </strong>This review summarizes recent advances in microglial biology across acute brain injury, neurodegenerative and demyelinating disorders, central nervous system infections, and psychiatric and neurodevelopmental diseases. Evidence from multiomics studies, genetic approaches, functional experiments, and emerging therapeutic strategies was integrated to evaluate mechanisms and translational challenges.</p><p><strong>Results: </strong>Microglial responses represent dynamic functional programs rather than fixed beneficial or detrimental phenotypes. Their effects on inflammation, phagocytosis, immune regulation, and tissue repair are determined by disease stage, anatomical location, and local microenvironment. Although microglia targeted therapies, including signaling modulation, depletion and repopulation, replacement strategies, and targeted delivery systems, show promise, clinical translation remains limited by insufficient human validation, model differences, and incomplete understanding of spatiotemporal regulation.</p><p><strong>Conclusions: </strong>Microglial function should be interpreted within a context dependent framework integrating cellular state, functional outcome, disease stage, and therapeutic timing. Future studies should focus on cell specific validation and human translational approaches to develop precise microglia directed therapies.</p><p><strong>Highlight: </strong>Microglial responses are dynamic functional programs shaped by disease context, anatomical location, and temporal progression rather than fixed phenotypes. Single cell and spatial omics reveal extensive microglial heterogeneity, but functional validation remains essential to distinguish molecular states from biological outcomes. Context guided microglial modulation, including targeted delivery, immune regulation, depletion, and replacement strategies, provides new opportunities for precision therapy.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":"e70839"},"PeriodicalIF":7.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988193","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 the tumour microenvironment: Harnessing border immunity for glioblastoma immunotherapy.","authors":"Lanjie Chen, Yixin Gao, Jian Zhong, Nu Zhang","doi":"10.1002/ctm2.70841","DOIUrl":"10.1002/ctm2.70841","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":"e70841"},"PeriodicalIF":7.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988203","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":"4-Hydroxytamoxifen induces a noncanonical ferroptosis in lung adenocarcinoma by targeting AKR1B10.","authors":"Hui Yang, Yanan Wang, Jiangbo Jin, Hanyan Xu, Yinshui Miao, Xiaojing Wu, Shengsong Chen, Tianyu Han, Qingyuan Zhan","doi":"10.1002/ctm2.70796","DOIUrl":"10.1002/ctm2.70796","url":null,"abstract":"<p><strong>Background: </strong>Lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality, and current therapies are limited by drug resistance and toxicity. Ferroptosis offers an attractive strategy for cancer therapy, but classical ferroptosis is iron‑dependent. Repurposing approved drugs offers a rapid strategy to identify novel anti‑LUAD agents, yet the mechanism by which 4‑Hydroxytamoxifen (4‑OHT) exerts estrogen receptor-independent anti‑tumour effects remains unclear.</p><p><strong>Methods: </strong>We performed a drug repurposing screen of 950 endogenous metabolites in LUAD cells. Anti‑tumour activity was validated in vitro and in vivo using LUAD cell lines and mouse models. Target identification and mechanistic studies employed LiP‑MS, pull-down SPR, CETSA, metabolomics, and enzyme activity assays. Clinical relevance was assessed via tissue microarrays and TCGA analysis. Drug synergy was quantified using the Chou-Talalay method.</p><p><strong>Results: </strong>4‑OHT inhibited LUAD cell proliferation with IC₅₀ values of 3.86 ± 0.26 µM to 13.58 ± 0.55 µM independent of estrogen receptor. It triggered noncanonical ferroptosis characterised by GSH depletion (reduced by about 60%), GPX4 downregulation, lipid peroxidation (about 2.5-fold increase), and iron independence. Mechanistically, 4‑OHT directly bound AKR1B10 (K_D(M) was 7.98e-06) and inhibited its enzymatic activity, leading to ACC1 degradation, lipid deficiency, and accumulation of toxic lipid‑derived carbonyls. AKR1B10 knockout abolished 4‑OHT‑induced cell death, while rescue restored sensitivity. Nanatinostat similarly targeted AKR1B10 and induced the same cell death modality. AKR1B10 upregulation in LUAD tissues correlated with reduced overall survival rates.</p><p><strong>Conclusion: </strong>This study demonstrates that 4‑OHT directly inhibits AKR1B10 enzymatic activity to induce a noncanonical ferroptosis in LUAD. AKR1B10 overexpression correlates with poor prognosis and chemoresistance in LUAD patients. Nonetheless, AKR1B10 inhibition warrants further investigation as a therapeutic strategy.</p><p><strong>Highlights: </strong>4‑OHT directly inhibits AKR1B10 enzymatic activity to induce noncanonical ferroptosis in LUAD. AKR1B10 sustains LUAD survival by stabilising ACC1 and detoxifying reactive carbonyl species (RCSs). Nanatinostat similarly targets AKR1B10 and elicits the same cell death modality. AKR1B10 overexpression correlates with poor prognosis and chemoresistance in LUAD.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":"e70796"},"PeriodicalIF":7.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13551091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905155","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":"Single-cell transcriptomic analysis reveals subtle fluctuations of oocyte cryopreservation on mouse early embryo development.","authors":"Yixin Ren, Qingyang Zhang, Fanqing Xu, Yao Li, Tianyi Liao, Mengyuan Zhao, Zhiqiang Yan, Xiaohui Zhu, Nan Wang, Peng Yuan, Gary D Smith, Jie Qiao, Jie Yan, Liying Yan, Qilong He","doi":"10.1002/ctm2.70801","DOIUrl":"10.1002/ctm2.70801","url":null,"abstract":"<p><strong>Background: </strong>Oocyte cryopreservation is widely used in assisted reproductive technology, but its effects on embryonic development remain a concern. This study aimed to determine whether oocyte cryopreservation induces transcriptional alterations at the early cleavage and blastocyst stages.</p><p><strong>Methods: </strong>We performed single-cell RNA sequencing on mouse Metaphase II oocyte and embryos at early/late 1 cell, early/late 2 cell, morula and blastocyst stages derived from cryopreserved (cryo) and fresh (fresh) oocytes. Transcriptomic profiles were compared between the two groups.</p><p><strong>Results: </strong>Global transcriptomes were highly similar between cryo and fresh blastocysts. Oocyte cryopreservation did not alter the sex ratio or the developmental progression through preimplantation development. In blastocysts, cryopreservation affected only a few individual genes. In both male and female blastocysts, although oocyte cryopreservation increased the proportion of low Xist-expressing cells, it did not disrupt X-linked gene dosage. In the inner cell mass (ICM) of blastocysts, a negative correlation between X-linked gene expression and cell cycle progression was identified, and this negative correlation was more pronounced in trophectoderm (TE) cells. Overall, this stage-dependent coordination remained unperturbed by cryopreservation. CellChat analysis revealed that the signalling interaction strength between ICM and TE also showed no significant changes in the cryo group.</p><p><strong>Conclusions: </strong>Oocyte cryopreservation does not severely disrupt overall transcriptional integrity, developmental potency and X-chromosome dosage compensation of embryos, but it may cause subtle molecular changes. These findings highlight the need for continued refinement of cryopreservation methods and further investigation into the sub-acute safety of assisted reproductive technology procedures.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":"e70801"},"PeriodicalIF":7.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13550515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905204","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":"Advances and challenges in immunotherapy for intrahepatic cholangiocarcinoma based on the tumour immune microenvironment.","authors":"Mengyao Chen, Shuofan Jin, Yuxuan Zhou, Jinkai Tong, Yufan Zhao, Quanjun Yang","doi":"10.1002/ctm2.70830","DOIUrl":"10.1002/ctm2.70830","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Intrahepatic cholangiocarcinoma (ICC) is a highly heterogeneous and aggressive malignancy originating from the intrahepatic bile duct epithelial cells. Despite advances in surgery, chemotherapy, targeted therapy, and immune checkpoint inhibitor (ICI)-based regimens, durable disease control remains limited by primary or acquired resistance and marked biological heterogeneity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Main body: &lt;/strong&gt;Immunotherapy, primarily based on ICIs, has shown clinical potential for advanced ICC; however, its activity is constrained by a highly immunosuppressive tumour microenvironment (TME), including desmoplastic stromal barriers, myeloid-cell-mediated suppression, impaired antigen presentation, cytokine- and chemokine-driven immune exclusion, and metabolic remodeling. This review summarizes the tumour immune microenvironment (TIME) of ICC, with emphasis on cellular crosstalk among stromal, myeloid, and lymphoid compartments, extracellular matrix remodeling, metabolic constraints, and immune-escape processes. We critically appraised first-line chemoimmunotherapy evidence from advanced biliary tract cancer (BTC) trials and interpreted its relevance to ICC according to clinical evidence, tumour location, molecular subtype, and biomarker context. Biomarkers are discussed according to their current level of clinical validation, and molecular alterations, such as FGFR2 fusions, IDH1 mutations, and BAP1/ARID1A alterations, are considered in relation to immune phenotypes and mechanism-guided combination hypotheses. Finally, we evaluated emerging approaches, including next-generation checkpoint inhibitors, antibody-drug conjugates, bispecific antibodies, CAR-T/CAR-macrophage (CAR-M)/CAR-natural killer (CAR-NK) cell therapies, cancer vaccines, and dendritic cell-based interventions, with particular attention paid to antigen heterogeneity, stromal trafficking barriers, manufacturing complexity, and the limited maturity of ICC-specific clinical evidence.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;By integrating the mechanism, clinical evidence, molecular subtype and translational limitations, this review provides a balanced framework for biomarker-guided precision immunotherapy in ICC.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Key points: &lt;/strong&gt;The clinical evidence and limitations of immunotherapy for intrahepatic cholangiocarcinoma are critically evaluated, with emphasis on ICC-specific interpretation of broader biliary tract cancer trials. The ICC tumour immune microenvironment is integrated into functional immune axes involving stromal, myeloid, lymphoid and metabolic regulation. Molecular subtypes and immune-related biomarkers provide a framework for biomarker-guided precision immunotherapy in ICC. Current ICC immunotherapy trials remain limited by heterogeneous designs, small ICC-specific cohorts and immature clinical evidence. Emerging immunotherapies, including next-generation checkpoint inhibitors, antibody-drug conjugates, cellular therapies and va","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 9","pages":"e70830"},"PeriodicalIF":7.9,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148929117","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}