Molecular Cancer最新文献

{"title":"Remodeling of the tumor microenvironment in muscle-invasive bladder cancer: insights from single-cell and spatial transcriptomics after neoadjuvant immunochemotherapy.","authors":"Guozhi Zhao,Yuanyuan Bai,Xin Chen,Junwu Li,Hai Chang,Yongtang Zhu,Haoyu Xu,Yiqing You,Gautam Sethi,Deyu Zuo,Wei Tang,Lei Yang,Weiyang He","doi":"10.1186/s12943-026-02738-y","DOIUrl":"https://doi.org/10.1186/s12943-026-02738-y","url":null,"abstract":"BACKGROUNDNeoadjuvant immunochemotherapy (nICT), defined in this study as PD-L1 blockade combined with cisplatin-based chemotherapy, provides substantial clinical benefits in muscle-invasive bladder cancer (MIBC). However, the tumor immune microenvironment (TIME) is highly heterogeneous, resulting in variable patient responses and persistent therapy resistance. This study investigates key immune cell subsets, intercellular communication networks, and spatial distributions within the TIME of MIBC, with a focus on cellular and spatial features associated with nICT response.METHODSPatients were classified into responder and non-responder groups according to RECIST 1.1-based radiological evaluation. Responders were defined as patients achieving complete or partial response, whereas non-responders were defined as patients with stable or progressive disease after adequate nICT exposure and evaluable imaging. Representative computed tomography images and fresh tissue samples were collected from four no-treatment controls (NT), three nICT responders (R), and three nICT non-responders (NR). Samples underwent single-cell RNA sequencing and spatial transcriptomics sequencing. Cell populations were annotated to assess infiltration abundance, cell-cell communication networks, and pseudotime trajectories. Resistance-associated cell subsets and their spatial niches were identified.RESULTSFollowing quality control, the tumor microenvironment (TME) was classified into ten major cell subsets based on canonical markers. Cross-sectional group comparative analyses showed significant remodeling of the TME in the NR and R groups. B-cell infiltration was elevated in the NR group, whereas macrophages, fibroblasts, and mast cells were enriched in the R group. Functional alterations in activated CD4 + T cells and impaired differentiation of naive CD8 + T cells were identified as key drivers of acquired therapy resistance. Accumulation of macrophage-derived CXCL8 was also observed as a resistance driver. Cancer-associated fibroblasts (CAFs) served as a physical barrier, contributing to the establishment of an immunosuppressive TME. Notably, strong spatial co-localization between macrophage-derived CXCL8 and CAFs was observed in NR tumors, suggesting a cooperative role in mediating resistance to nICT. Further cell-cell communication analysis using spatial transcriptomics indicated that SPP1 signaling from macrophages (CXCL8) to CAFs contributes to TME reprogramming and resistance to nICT.CONCLUSIONThe integrated analysis identifies distinct immunological features that underlie differential nICT responses in MIBC. These findings provide a theoretical basis for optimizing personalized neoadjuvant therapy strategies.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"348 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148462445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutation-specific dynamics of dedifferentiation trajectories and tumor-stromal interactions in thyroid cancer.","authors":"Eun Hye Joo,Young Shin Song,Han Sai Lee,Gyeongseo Jung,Eun-Jae Chung,Su-Jin Kim,Yoo Hyung Kim,Sun Wook Cho,Hongyoon Choi,Jae-Kyung Won,Woong-Yang Park,Young Joo Park","doi":"10.1186/s12943-026-02699-2","DOIUrl":"https://doi.org/10.1186/s12943-026-02699-2","url":null,"abstract":"Progression from differentiated thyroid cancer to anaplastic thyroid cancer (ATC) involves profound epithelial plasticity and remodeling of the tumor microenvironment (TME), but how BRAFV600E and RAS driver mutations shape these processes remains unclear. Here, we integrated single-nucleus RNA-seq, spatial transcriptomics, and bulk RNA-seq across BRAFV600E- and RAS-driven thyroid tumors to delineate mutation-specific progression trajectories. BRAFV600E-driven tumors exhibited a gradual dedifferentiation trajectory with immune pathway activation, whereas RAS-driven tumors displayed abrupt transitions characterized by aneuploidy, epithelial-mesenchymal transition, hypoxia, and extracellular matrix remodeling. Cancer-associated fibroblasts (CAFs) emerged as key regulators, with mutation-specific ligand-receptor interactions: integrin-based signaling predominated in BRAFV600E-mutant ATCs, while PLAU-PLAUR, TNFSF10-TNFRSF10B, and AREG-EGFR were additionally enriched in RAS-driven ATCs. These CAF-epithelial circuits were spatially validated and associated with poor prognosis. Together, our findings reveal mutation-dependent epithelial and TME dynamics associated with thyroid cancer dedifferentiation and highlight the potential importance of molecular-tailored approaches in the management of advanced thyroid cancer.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"76 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148451452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma proteomic and metabolomic profiling reveals molecular features relevant to neoadjuvant therapy response in locally advanced esophageal squamous cell carcinoma.","authors":"Chu Xiao,Ziqin Deng,Guochao Zhang,Zhenlin Yang,Long Zhang,Hongfei Yin,Tao Fan,Di Wang,Yixiao Liu,Wenpeng Cai,Yu Ji,Jia Li,Tianle Liao,Chunxiang Li,Jie He","doi":"10.1186/s12943-026-02733-3","DOIUrl":"https://doi.org/10.1186/s12943-026-02733-3","url":null,"abstract":"BACKGROUNDNeoadjuvant therapy (NAT) followed by radical surgery is the standard treatment for locally advanced esophageal squamous cell carcinoma (LA-ESCC), yet many patients fail to achieve pathologic complete response (pCR). Predictive biomarkers and biological mechanisms underlying NAT resistance remain elusive. We aimed to address this challenge through longitudinal multi-omics profiling of patient plasma during NAT.METHODSWe performed longitudinal plasma proteomic and metabolomic analyses in a discovery cohort of patients with LA-ESCC (n = 40) receiving neoadjuvant chemotherapy (nCT) or neoadjuvant immunochemotherapy (nICT) to reveal molecular features relevant to treatment response. Predictive biomarkers for pCR were assessed in plasma samples from an independent validation cohort (n = 93) by ELISA. Mechanistic studies were conducted through in vitro cell co-culture, in vivo mouse experiments, and analysis of ESCC tissue samples from another validation cohort (n = 33).RESULTSMulti-omics analysis revealed distinct molecular profiles between treatment responders and non-responders. Metabolomic profiling revealed dynamic treatment-associated changes in amino acid and lipid metabolism during NAT, and proteomic profiling highlighted baseline differences related to neutrophil activity and inflammatory responses. DEFA1 was validated as an unfavorable predictive biomarker for achieving pCR after nICT. Mechanistic studies demonstrated that DEFA1 fosters an immunosuppressive microenvironment by promoting myeloid-derived suppressor cell (MDSC) differentiation and impairing CD8+ T cell cytotoxicity.CONCLUSIONSThis study delineates the longitudinal plasma multi-omic landscape associated with NAT response in LA-ESCC and identifies DEFA1 as a predictive biomarker and potential therapeutic target for overcoming immunotherapy resistance.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"22 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148451448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Long noncoding RNA GAS5 inhibits progression of colorectal cancer by interacting with and triggering YAP phosphorylation and degradation and is negatively regulated by the m⁶A reader YTHDF3.","authors":"Wen Ni, Su Yao, Yunxia Zhou, Yuanyuan Liu, Piao Huang, Aijun Zhou, Jingwen Liu, Liheng Che, Jianming Li","doi":"10.1186/s12943-026-02719-1","DOIUrl":"10.1186/s12943-026-02719-1","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13355347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422719","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":"TBL1XR1 mutations promoted tumor progression in diffuse large B-cell lymphoma through impairing nature killer cytotoxicity via the MYC-CD47/PD-L1 axis.","authors":"Yue Zhu,Yi-Ge Shen,Wei Tang,Zhong Zheng,Si-Yuan Chen,Yao-Hui Huang,Di Fu,Shu Cheng,Peng-Peng Xu,Li Wang,Jiahao Chen,Meng-Meng Ji,Wei-Li Zhao","doi":"10.1186/s12943-026-02724-4","DOIUrl":"https://doi.org/10.1186/s12943-026-02724-4","url":null,"abstract":"TBL1XR1 is frequently mutated in diffuse large B-cell lymphoma (DLBCL), yet its functional impact on tumor microenvironment remains poorly defined. In this study, we characterized TBL1XR1 mutations in a cohort of 1842 newly diagnosed DLBCL patients, identifying mutations in 9.4% of cases (n = 173). These mutations correlated with clinically aggressive features, including older age (> 60 years), high-risk International Prognostic Index, enrichment in non-GCB subtypes, as well as inferior progression-free and overall survival. Mechanistically, TBL1XR1 mutations enhanced H3K27ac levels at the MYC promoter, increased MYC expression and subsequently up-regulated its immune-regulatory targets CD47 and PD-L1. This axis impaired natural killer (NK) cytotoxicity, facilitating immune escape and tumor progression. In a murine A20 B-lymphoma model, tumors harboring Tbl1xr1 mutations exhibited up-regulated MYC, CD47, and PD-L1 expression, resulting in NK cell dysfunction and tumor growth acceleration via the MYC-CD47/PD-L1 axis. Dual blockade of CD47 and PD-L1 restored NK cell-mediated tumor immunity, triggering rapid regression of Tbl1xr1-mutated tumors. Taken together, our findings identified TBL1XR1 mutations as a microenvironment-related mechanism of DLBCL progression and provided clinical rationale of co-targeting CD47 and PD-L1 to treat this genetically defined subset.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"31 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148416602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Long noncoding RNA TLNC1 promotes the growth and metastasis of liver cancer via inhibition of p53 signaling.","authors":"Kefei Yuan, Jiang Lan, Lin Xu, Xuping Feng, Haotian Liao, Kunlin Xie, Hong Wu, Yong Zeng","doi":"10.1186/s12943-026-02710-w","DOIUrl":"10.1186/s12943-026-02710-w","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13352764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422777","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: The Wnt inhibitory factor 1 restoration in prostate cancer cells was associated with reduced tumor growth, decreased capacity of cell migration and invasion and a reversal of epithelial to mesenchymal transition.","authors":"David S Yee, Yaxiong Tang, Xuesen Li, Zhongbo Liu, Yi Guo, Samia Ghaffar, Peter McQueen, Dash Atreya, Jun Xie, Anne R Simoneau, Bang H Hoang, Xiaolin Zi","doi":"10.1186/s12943-026-02714-6","DOIUrl":"10.1186/s12943-026-02714-6","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":""},"PeriodicalIF":42.2,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13343620/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148412461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autophagy in cancer - functional plasticity, therapeutic paradox, and the road to precision modulation: a comprehensive review.","authors":"Jingjing Liu,Peng Wu,Dongyu Li,Xuanyu Gu,Bohui Zhao,Ruijie Ma,Binghua Tan,Dexin Shang,Junhan Zhou,Chuqi Lin,Nan Sun,Chaoqi Zhang,Jie He","doi":"10.1186/s12943-026-02633-6","DOIUrl":"https://doi.org/10.1186/s12943-026-02633-6","url":null,"abstract":"Autophagy is an evolutionarily conserved lysosomal degradation pathway. In cancer, its role is paradoxical: it functions as a tumor-suppressive gatekeeper during initiation in part by preserving genomic stability, but it is frequently co-opted by established tumors to maintain metabolic fitness and therapeutic resistance. Early clinical efforts using broad, non-selective lysosomal inhibition (e.g., chloroquine) produced mixed outcomes and toxicities, prompting a paradigm shift toward modular, context-specific modulation.This review synthesizes the dynamic spatiotemporal evolution of autophagy in tumorigenesis, and characterizes it as an adaptable evolutionary trajectory governed by stress, tumor genotype, and microenvironmental context. We outline four conceptual pillars: genotype-defined modular networks, dynamic spatiotemporal adaptation, autophagy as an immunometabolic rheostat, and rational therapeutic modulation. Importantly, autophagy exerts cell-type-specific effects-promoting immune evasion in tumor cells while remaining indispensable for lymphocyte fitness. To address this paradox, we evaluate the transition from empirical global blockade to precision-guided intervention, including pathway-selective modulators, exploitation of selective vulnerabilities, and advanced targeted degradation technologies. Autophagy in cancer is a highly dynamic, context-dependent variable. Therapeutic control requires movement beyond universal flux inhibition toward pathway-specific, biomarker-guided interventions that match a tumor's distinct autophagic dependencies. Integration of dynamic monitoring with precise delivery systems may allow active modulation of the tumor microenvironment, transforming autophagy from a tumor resilience mechanism into an exploitable therapeutic vulnerability.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"224 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148400556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic immunosuppression limits NK cell therapy efficacy in pancreatic cancer.","authors":"Chunbo He,Dezhen Wang,Tuo Hu,Daisy Gonzalez,Ravi Thakur,Damian P Matysniak,Ryan J King,Sai Sundeep Kollala,Spas Dimitrov Markov,Yuki Fujii,Gullanki Naga Venkata Charan Tej,Junzhang Zhao,Longyang Jin,Rebecca Oberley-Deegan,Surendra K Shukla,Xin A Zhang,Jacob E Friedman,Pankaj K Singh,Michael A Hollingsworth,Marina Pasca di Magliano,Howard C Crawford,Kamiya Mehla","doi":"10.1186/s12943-025-02340-8","DOIUrl":"https://doi.org/10.1186/s12943-025-02340-8","url":null,"abstract":"Nature killer (NK) cell plays a critical role in cancer immunosurveillance and is considered a potent immunotherapeutic tool for many cancers, including pancreatic ductal adenocarcinomas (PDACs). Increasing evidence suggests that cancer occurs with systemic immune perturbations. However, the effects of PDAC tumor burden on systemic NK cells remain poorly understood. PDAC tumor-bearing mice display decreased frequency and dysfunction of NKs the spleens. We identified an increase in Gr-1+ myeloid cells within the spleens, which negatively impacts both endogenous and adoptively transferred NK cell frequency and function. Apolipoprotein E (ApoE), a lipid metabolism regulator, is upregulated in Gr-1+ myeloid cells of tumor-bearing mice, promoting lipid oxidation and reactive oxygen species (ROS) generation. Genetic knockout of Apoe in Gr-1+ myeloid cells abrogate their suppressive effects on NK cell function. Furthermore, treatment with lipid metabolism inhibitors restores endogenous and adoptively transferred NKs' effector function in the spleens and tumor microenvironment. These studies underscore the importance of understanding preexisting systemic alterations in PDAC patients before applying NK cell-based immunotherapies.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"230 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148408322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting HASPIN-mediated H3T3 phosphorylation disrupts an epigenetic-kinesin axis to suppress colorectal cancer mitotic progression.","authors":"Tong Wu,Yaguang Zhang,Sicheng Liu,Chensong Zhang,Yang Zhang,Qiuye Luo,Dian Gao,Yang Meng,Yixin Jiang,Junhong Han","doi":"10.1186/s12943-026-02723-5","DOIUrl":"https://doi.org/10.1186/s12943-026-02723-5","url":null,"abstract":"Chemoresistance remains a major barrier in colorectal cancer (CRC) therapy. Through epigenetic compound screening in patient-derived organoids (PDOs), we identified CX6258.HCl as a potent growth inhibitor. Treatment with CX6258.HCl significantly inhibited cell mitosis and induced apoptosis in CRC cell lines. Mechanistically, CX6258.HCl binds the D687 residue within HASPIN's kinase domain, suppressing H3T3 phosphorylation (H3T3ph). This triggers an epigenetic cascade: loss of H3T3ph upregulates demethylase KDM5B pre-mRNA, depleting H3K4me3 at promoters of Kinesin family member (KIFC1/KIF10/KIF14). Consequently, microtubule dynamics are disrupted, leading to mitotic arrest. Target specificity was validated genetically via HASPIN-D687A mutation. In vivo, CX6258.HCl suppressed CRC xenograft growth and further enhanced 5-FU-mediated tumor suppression without obvious histological injury in major organs. Clinically, elevated H3T3ph levels in human CRC tissues were associated with Ki67-positive proliferative tumor regions, suggesting that H3T3ph may represent a proliferation-associated marker in CRC. Together, our findings identify the HASPIN/H3T3ph-KDM5B-H3K4me3-KIF axis as a targetable antimitotic pathway and support therapeutic inhibition of HASPIN/H3T3ph as a potential strategy for CRC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"137 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148400564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}