Molecular Cancer最新文献

{"title":"Demystifying the cGAS-STING pathway: precision regulation in the tumor immune microenvironment","authors":"Qingyang Wang, Yang Yu, Jing Zhuang, Ruijuan Liu, Changgang Sun","doi":"10.1186/s12943-025-02380-0","DOIUrl":"https://doi.org/10.1186/s12943-025-02380-0","url":null,"abstract":"The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway serves as an immune sentinel for cytosolic DNA, recognizing double-stranded DNA (dsDNA) derived from abnormally localized nuclear DNA or mitochondrial DNA (mtDNA), and plays a pivotal role in innate immune responses and tumor immune surveillance. Conventional antitumor therapies induce genomic instability and mitochondrial stress, leading to the release of nuclear DNA and mtDNA into the cytosol, thereby activating the cGAS-STING pathway. This activation triggers the production of type I interferons (IFN-I) and pro-inflammatory cytokines, which reshape the tumor immune microenvironment (TIME). However, the complexity of TIME reveals a “double-edged sword” effect of cGAS-STING signaling: while it activates antitumor immune responses, it also promotes immune escape and metastasis through the regulation of immunosuppressive cells and stromal components. This review comprehensively delineates the differential regulatory mechanisms of the pathway within TIME constituents, highlighting its multifaceted roles in tumor immunity. Furthermore, it reviews recent advances and challenges in targeting the cGAS-STING pathway for cancer immunotherapy, with the aim of advancing cGAS-STING signaling modulation as a key therapeutic strategy to reprogram TIME and overcome immunosuppression in antitumor treatment.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"23 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269043","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":"Enhancing radiotherapy-induced anti-tumor immunity via nanoparticle-mediated STING agonist synergy","authors":"Qian Zeng, Min Liu, Ziqi Wang, Rongrong Zhou, Kelong Ai","doi":"10.1186/s12943-025-02366-y","DOIUrl":"https://doi.org/10.1186/s12943-025-02366-y","url":null,"abstract":"Radiotherapy (RT) remains a cornerstone treatment for over 50% of cancer patients, primarily via ionizing radiation-induced DNA damage to exert therapeutic effects. Notably, emerging studies have revealed its additional capacity to activate systemic anti-tumor immune responses through inducing immunogenic cell death (ICD) and activating the cGAS-STING pathway, further expanding its therapeutic potential. However, its efficacy is often limited by immunosuppressive tumor microenvironment (TME). Additionally, while RT can activate the cGAS-STING pathway, this activation remains transient and suboptimal, failing to sustain robust anti-tumor immunity. Therefore, combining RT with STING agonists may benefit traditional therapy by amplifing tumor immunogenicity and counteracting immune evasion. Despite promising results, challenges such as off-target toxicity, poor cell membrane permeability and poor bioavailability, remain obstacles to clinical translation of conventional STING agonists. Nanomedicine offers a promising approach by enabling targeted delivery of STING agonists and amplifying RT-induced DNA damage through nanoscale radiosensitizers. In this review, we provide a detailed discussion of the immune-stimulatory and immune-suppressive effects of RT, as well as the mechanisms and biological effects of selectively activating the cGAS-STING pathway in key TME components. On this basis, we further explore recent advancements in nano-STING agonists-mediated anti-tumor immunity in synergy with RT. This combinatorial approach achieves dual radiosensitization and immunostimulation, ultimately driving immune memory formation and TME reprogramming. Finally, the application prospects and challenges of nano-STING agonists-based immunotherapy are also discussed from the perspective of clinical translation.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"24 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260485","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":"Anlotinib combined with benmelstobart as a chemo-free first-line treatment in advanced esophageal squamous cell carcinoma: an exploratory multicenter, single-arm phase II clinical trial","authors":"Xiangrui Meng, Xiuli Yang, Yonggui Hong, Wenkang Wang, Zhiye Zhang, Jin Xia, Yunfang Chen, Yue Zhou, Taiying Lu, Min Song, Zhengzheng Shan, Tao Wu, Weilong Wu, Ling Shen, Lulu Guan, Mingying Ma, Lisen Wang, Xi Luo, Dao Xin, Yihui Ma, Guozhong Jiang, Yu Qi, Binghua Jiang, Daoyu Zhang, Biao Hu, Xiaoying Wu, Zuofu Peng, Feng Wang","doi":"10.1186/s12943-025-02376-w","DOIUrl":"https://doi.org/10.1186/s12943-025-02376-w","url":null,"abstract":"No combined antiangiogenic and PD-1/PD-L1 blockade therapy has been investigated as a chemo-free first-line treatment for advanced esophageal squamous cell carcinoma (ESCC). This study evaluates the efficacy and safety of anlotinib combined with benmelstobart as a chemo-free treatment in previously untreated advanced ESCC, and identifies potential predictive biomarkers using next-generation sequencing (NGS). ALTER-E-003, a single-arm, open-label phase II trial, enrolled patients with advanced ESCC across five Chinese centers. Patients received oral anlotinib 12 mg daily on days 1–14 per three-week cycle, with benmelstobart 1200 mg infused on day 1 of each cycle for up to 24 months. Thereafter, patients received anlotinib maintenance therapy. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR), and safety. NGS and fluorescent multiplex immunohistochemistry (mIHC) were performed on tumor specimens. Of 53 screened patients, 46 completed the study. The confirmed ORR was 56.5% (95% CI 41.1–71.1), and DCR was 91.3% (95% CI 79.2–97.6). Median PFS was 15.74 months (95% CI 9.03–21.91). Treatment-related adverse events occurred in 93.5% of patients, with 28.3% experiencing grade 3 or higher events. NGS revealed a novel predictive mutational signature (TP53+/FAT1+/NOTCH3-) that was associated with better ORR (65.6% versus 11.1%, P < 0.001), longer median PFS (17.91 versus 5.32 months, P = 0.005) and improved OS (P = 0.006). First-line anlotinib-benmelstobart combination demonstrated durable responses and acceptable safety in ESCC patients. Exploratory biomarker analyses identified a TP53+/FAT1+/NOTCH3- mutational signature potentially associated with improved outcomes, though further validation in randomized trials is warranted. NCT05038813.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"36 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260486","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":"Wnt/β-catenin mediated signaling pathways in cancer: recent advances, and applications in cancer therapy","authors":"Xiuzhu Wu, Haiying Que, Qingfang Li, Xiawei Wei","doi":"10.1186/s12943-025-02363-1","DOIUrl":"https://doi.org/10.1186/s12943-025-02363-1","url":null,"abstract":"The Wnt/β-catenin signaling pathway is a highly conserved signaling pathway closely linked to cancer development through various biological processes, including oncogenic transformation, genomic instability, cancer cell proliferation, stemness, metabolism, cell death, immune regulation, and metastasis. Notably, its activation plays a crucial role in drug resistance to chemotherapy, targeted therapy and immunotherapy. Recent advances in drug development have identified several targeted inhibitors acting at key nodal points of this pathway, with some demonstrating synergistic efficacy when combined with immunotherapeutic agents. This review provides a comprehensive analysis of current understanding regarding the Wnt/β-catenin pathway in malignancy, emphasizing its multifaceted roles in tumor initiation, therapeutic resistance, and immune regulation. Additionally, we summarized the clinical performance of combination therapies targeting the Wnt/β-catenin pathway in conjunction with chemotherapy, targeted therapy, and immunotherapy. Although clinical development remains at a relatively early stage, pharmacological modulation of Wnt/β-catenin signaling offers considerable potential as a novel therapeutic paradigm in precision oncology.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"58 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252010","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":"Differential susceptibility and role for senescence in CART cells based on costimulatory domains","authors":"Ismail Can, Elizabeth L. Siegler, Olivia L. Sirpilla, Claudia Manriquez-Roman, Kun Yun, Carli M. Stewart, Jennifer M. Feigin, Makena L. Rodriguez, Omar L. Gutierrez-Ruiz, Ekene J. Ogbodo, Truc N. Huynh, Brooke L. Kimball, Long K. Mai, Mehrdad Hefazi, Lionel Kankeu Fonkoua, Hong Xia, Imene Hamaidi, Berke Alkan, Fatih Sezer, H. Atakan Ekiz, R. Leo Sakemura, Saad S. Kenderian","doi":"10.1186/s12943-025-02371-1","DOIUrl":"https://doi.org/10.1186/s12943-025-02371-1","url":null,"abstract":"Despite the success of chimeric antigen receptor T (CART) cell therapy in hematological malignancies, durable remissions remain low. Here, we report CART senescence as a potential resistance mechanism in 41BB-costimulated CART cell therapy. To mimic cancer relapse, we utilized an in vitro model with repeated CART cell activation cycles followed by rest periods. Using CD19-targeted CART cells with costimulation via 4-1BB-CD3ζ (BBζ) or CD28-CD3ζ (28ζ), we showed that CART cells undergo functional, phenotypical, and transcriptomic changes of senescence, which is more prominent in BBζ. We then utilized two additional independent strategies to induce senescence through MYC activation and irradiation. Induction of senescence impaired BBζ activity but improved 28ζ activity in preclinical studies. These findings were supported by analyses of independent patient data sets; senescence signatures in CART cell products were associated with non-response to BBζ but with improved clinical outcomes in 28ζ treatment. In summary, our study identifies senescence as a potential mechanism of failure predominantly in 41BB-costimulated CART cells. We identified senescence as a cause of failure in CART cell therapy, predominantly in 4-1BB-costimulated CART cells.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"31 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252009","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":"CREPT is required for the metastasis of triple-negative breast cancer through a co-operational-chromatin loop-based gene regulation","authors":"Jianghua Li, Lu Xu, Jiayu Wang, Xuning Wang, Yuting Lin, Alex Yutian Zou, Fangli Ren, Yinyin Wang, Jun Li, Zhijie Chang","doi":"10.1186/s12943-025-02361-3","DOIUrl":"https://doi.org/10.1186/s12943-025-02361-3","url":null,"abstract":"Triple-negative breast cancer (TNBC) is recognized for its aggressiveness, yet the mechanism underlying metastasis remains unclear. Here, we report that CREPT/RPRD1B, which exhibits somatic gene copy-number amplifications and elevated expression, correlates with poor patient survival and drives TNBC metastasis. We demonstrate that CREPT alters three-dimensional genome structures in topologically-associating domain (TAD) status and chromatin loops via occupying promoters and enhancers. Specifically, CREPT mediates 1082 co-operational chromatin loops configured by enhancer-promoter and promoter-termination loops, which are validated by HiChIP analyses and visualized by Tn5-FISH experiments. These loops orchestrate RNAPII loading and recycling to enhance the metastatic gene expression. Disruption of these co-operational loops using CRISPR-dCas9 suppresses TNBC metastasis in vivo. Furthermore, depletion of CREPT using an AAV-based shRNA blocks TNBC metastasis in both preventative and therapeutic mouse models. We propose that targeting CREPT to disrupt the co-operational chromatin loop structures represents a promising therapeutic strategy for metastatic TNBC. • Somatic CREPT gene copy-number amplifications with elevated expression occur in the metastatic triple-negative breast cancer (TNBC) and correlate with poor patient survival • CREPT mediates 1082 co-operational chromatin loops configured by enhancer-promoter and promoter-termination loops • CREPT-mediated co-operational chromatin loops regulate metastatic genes during the metastasis of TNBC • Depleting CREPT by adeno-associated virus (AAV) blocks TNBC metastasis in preventative and therapeutic mouse models","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"23 6 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144252011","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":"Nanomedicine in Cancer Therapeutics: Current Perspectives from Bench to Bedside","authors":"K. M. Abdullah, Gunjan Sharma, Ajay P. Singh, Jawed A. Siddiqui","doi":"10.1186/s12943-025-02368-w","DOIUrl":"https://doi.org/10.1186/s12943-025-02368-w","url":null,"abstract":"Cancer is among the leading causes of death worldwide, with projections indicating that it will claim 35 million lives by the year 2050. Conventional therapies, such as chemotherapy and immune modulation, have reduced cancer mortality to some extent; however, they have limited efficacy due to their broad mode of action, often resulting in cytotoxic effects on normal cells along with the malignant tissues, ultimately limiting their overall optimal therapeutic efficacy outcomes. Rapid advances in nanotechnology and an evolving understanding of cancer mechanisms have propelled the development of a diverse array of nanocarriers to vanquish the hurdles in achieving sophisticated drug delivery with reduced off-target toxicity. Nanoformulations can deliver the anti-cancer agents precisely to the tumor cell by integrating a multitarget approach that allows for tissue-, cell-, or organelle-specific delivery and internalization. Despite the immense interest and unmatched advancements in modern oncology equipped with nanomedicines, only a few nanoformulations have successfully translated into clinical settings. A major reason behind this shortcoming is the lack of a rationale design incorporating smart, responsive targeting features, leading to a compromised therapeutic window due to inefficient internalization or erroneous intracellular localization with unsuccessful payload release. This review aims to summarize the recent perspective of nanomedicine and its translation to clinical practice, with a particular focus on the evolution of strategies used in tumor targeting from traditional EPR-based passive mechanisms to advanced active and multi-stage approaches. We highlight the coupling of organelle-specific and stimuli-responsive nanocarriers, discuss the potential of biomimetic and cell-mediated delivery systems, and also shed light on technologies such as microfluidics, tumor-on-chip models, and AI-assisted synthesis. Finally, this review explores translational hurdles ranging from biological and manufacturing challenges to regulatory bottlenecks and outlines how innovative modeling systems and engineering solutions can bridge the gap from bench to bedside in cancer nanotherapeutics.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"6 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144238102","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":"Exosomes in cancer nanomedicine: biotechnological advancements and innovations","authors":"Jacky J. J. Liu, Duanrui Liu, Sally K. Y. To, Alice S. T. Wong","doi":"10.1186/s12943-025-02372-0","DOIUrl":"https://doi.org/10.1186/s12943-025-02372-0","url":null,"abstract":"​​Exosomes, as natural intercellular messengers, are gaining prominence as delivery vehicles in nanomedicine, offering a superior alternative to conventional synthetic nanoparticles for cancer therapeutics. Unlike lipid, polymer, or metallic nanoparticles, which often face challenges related to immunogenicity, targeting precision, and off-tumor toxicity, exosomes can effectively encapsulate a diverse range of therapeutic agents while exhibiting low toxicity, favorable pharmacokinetics, and organotropic properties. This review examines recent advancements in exosome bioengineering over the past decade. Innovations such as microfluidics-based platforms, nanoporation, fusogenic hybrids, and genetic engineering have significantly improved loading efficiencies, production scalability, and pharmacokinetics of exosomes. These advancements facilitate tumor-specific cargo delivery, resulting in substantial improvements in retention and efficacy essential for clinical success. Moreover, enhanced biodistribution, targeting, and bioavailability—through strategies such as cell selection, surface modifications, membrane composition alterations, and biomaterial integration—suggests a promising future for exosomes as an ideal nanomedicine delivery platform. We also highlight the translational impact of these strategies through emerging clinical trials. Additionally, we outline a framework for clinical translation that focuses on: cargo selection, organotropic cell sourcing, precision loading methodologies, and route-specific delivery optimization. In summary, this review emphasizes the potential of exosomes to overcome the pharmacokinetic and safety challenges that have long impeded oncology drug development, thus enabling safer and more effective cancer treatments.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"478 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144236977","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":"The EGR1-mediated lncRNA TENM3-AS1 potentiates gastric cancer metastasis via reprogramming fatty acid metabolism","authors":"Yuhui Tang, Baiwei Zhao, Wanchuan Wang, Haoming Chen, Junsheng Zhang, Yi Xie, Yongming Chen, Feizhi Lin, Yuanfang Li, Xiaohui Zhai, Wen Zhou","doi":"10.1186/s12943-025-02341-7","DOIUrl":"https://doi.org/10.1186/s12943-025-02341-7","url":null,"abstract":"Long non-coding RNAs (lncRNAs) are essential modulators in tumor progression. While fatty acid (FA) metabolism can potentiate tumorigenesis, colonization, and metastasis, the roles of lncRNAs in reprograming FA metabolism and regulating gastric cancer (GC) metastasis remain elusive. Whole RNA-sequencing and in silico analyses were conducted to identify clinically significant lncRNAs involved in GC metastasis. Among the identified lncRNAs, we focused on the novel lncRNA TENM3-AS1. RT-qPCR and FISH analyses revealed an increased expression of TENM3-AS1 in GC cell lines and patients. In vitro and in vivo functional experiments validated the effects of TENM3-AS1 to GC metastasis and the reprogramming of FA metabolism. ChIP, Biotinylated RNA pull-down, RIP, CHX-chase assay, ubiquitination assay, and RNA stabilization assay were employed to perceive the mechanisms underlying the effects of TENM3-AS1 in GC cells. TENM3-AS1 expression was significantly elevated in metastatic tumors and advanced primary tumors of GC patients. This increased expression was also associated with a worsened overall survival and progression-free survival. Functionally, TENM3-AS1 enhanced the migration and invasiveness of GC cells in vitro, promoted tumorigenesis and liver metastasis in vivo, and increased FA biosynthesis in GC cells. Mechanistically, our studies showed that the transcription factor EGR1 activated TENM3-AS1, which in turn upregulated the expression of FASN and hnRNPK. Furthermore, TENM3-AS1 interacted with and stabilized hnRNPK by increasing its deubiquitination. This interaction reprogrammed FA metabolism and promoted GC progression by increasing FASN mRNA stability through hnRNPK. In this study, by comparing lncRNA sequencing data from paired primary and peritoneal metastatic tumors and public transcriptome data from non-metastatic and metastatic samples, we clarified a novel lncRNA, TENM3-AS1. It was found that TENM3-AS1 was aberrantly activated in metastatic and advanced primary tumors, and was strongly correlated with a shorter survival in GC patients. Our study reveals the EGR1/TENM3-AS1/ hnRNPK/FASN axis as a novel curative target in metastatic GC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"138 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144228828","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":"Integrative multi-omics analysis reveals the LncRNA 60967.1–PLCD4–ATRA axis as a key regulator of colorectal cancer progression and immune response","authors":"Yiyi Chen, Ningning Zhao, Lingna Xu, Xiya Jia, Fang Liu, Jian Huang, Xuhua Li, Yunfei Wang, Chuanxi Lai, Yanbin Shen, Fei Wang, Yiming Lv, Xuefeng Huang, Fan Zhang, Hongcang Gu, Sheng Dai","doi":"10.1186/s12943-025-02359-x","DOIUrl":"https://doi.org/10.1186/s12943-025-02359-x","url":null,"abstract":"Colorectal cancer (CRC) is a major global health concern, characterized by high morbidity and mortality rates. CRC progression involves intricate molecular networks that remain incompletely understood. In this study, we conducted an integrative multi-omics analysis of transcriptomic, proteomic, and metabolomic profiles from CRC tissues and matched normal adjacent tissues (NATs). Our analysis revealed 1,394 differentially expressed long non-Coding RNAs (lncRNAs), 2,788 genes, 548 proteins, and 91 metabolites. A significant interaction network comprising 22 lncRNAs, 14 mRNAs/proteins, and 9 metabolites was identified, among which lncRNA 60967.1 emerged as a pivotal regulator. Functional validation demonstrated that lncRNA 60967.1 is markedly downregulated in CRC cell lines and patient tissues. Overexpression of lncRNA 60967.1 restored expression of the tumor suppressor PLCD4 and increased levels of all-trans retinoic acid (ATRA). This modulation enhanced IFN-γ-induced apoptosis and increased expression of the IFN-γ receptor subunit IFNGR1, thereby partially reversing IFN-γ resistance. In murine models, lncRNA 60967.1 overexpression promoted immune cell infiltration and synergized with anti–PD-1 therapy to inhibit tumor growth. Collectively, our findings uncover a novel lncRNA-mRNA/protein-metabolite network, the lncRNA 60967.1-PLCD4-ATRA axis, that plays a critical role in CRC progression and immune modulation, offering promising therapeutic targets for improved treatment efficacy. Colorectal cancer (CRC) is characterized by substantial genetic and epigenetic heterogeneity, underscoring the need for novel therapeutic targets. While immunotherapy has led to significant advancements in cancer treatment, approximately 85% of CRC patients exhibit resistance due to different genetic and epigenetic features. Multi-omics approaches, which integrate data across genomic, proteomic, and metabolomic layers, have emerged as powerful tools for elucidating disease mechanisms. In this study, we conducted multi-omics analyses on tumor and adjacent normal tissues from 13 CRC patients. Complementary in vitro and in vivo experiments demonstrated that lncRNA 60967.1 regulates the PLCD4/ATRA axis and modulates the immune response to anti-PD-1 therapy, thereby promoting CRC progression. Our findings reveal a novel regulatory network involving lncRNA, PLCD4, and ATRA, providing a potential new target for CRC therapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"45 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144228829","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}