Molecular Cancer最新文献

{"title":"Advances and obstacles of T cell-based immunotherapy in gynecological malignancies","authors":"Xi Zhao, Jialing Ran, Shenglong Li, Jinxin Chen","doi":"10.1186/s12943-025-02411-w","DOIUrl":"https://doi.org/10.1186/s12943-025-02411-w","url":null,"abstract":" T cell-mediated immunotherapy has revolutionized oncology by enabling precision immune responses against malignant cells. Chimeric Antigen Receptor (CAR) T-cell therapy, which involves genetically reprogramming T lymphocytes to recognize tumor-specific antigens, has shown clinical success in hematologic malignancies and is expanding its potential in solid tumors. Gynecological cancers, including ovarian, cervical, and endometrial carcinomas, present persistent therapeutic challenges due to their aggressive recurrence patterns and limited responses to conventional therapies in advanced disease stages. This review offers a comprehensive analysis of CAR-T cell therapy advancements in gynecologic oncology, examining fundamental biological mechanisms of tumor-immune interactions, clinical progress in target antigen validation, and innovative approaches to counter immunosuppressive tumor microenvironments. Key challenges specific to these malignancies are discussed, such as molecular heterogeneity in endometrial tumors, ascites-mediated T-cell dysfunction in ovarian cancer (OC), and viral antigen dynamics in HPV- driven cervical carcinomas. Recent clinical evidence shows improved therapeutic outcomes through optimized CAR architectures and preconditioning regimens, with objective response rates demonstrating progressive enhancement across successive clinical trial generations. The discussion addresses ongoing limitations regarding treatment durability and manufacturing consistency while exploring emerging solutions such as synthetic biology approaches and multi-omics guided antigen selection. By integrating preclinical insights with translational clinical data, this work establishes a strategic framework for advancing adoptive T-cell therapies in gynecologic oncology, emphasizing the synergistic potential of combining CAR-T technology with personalized neoantigen vaccines and microenvironment-reprogramming agents. These collective advances underscore the transformative prospects of engineered T-cell immunotherapies while providing actionable strategies to overcome the unique biological barriers inherent to female reproductive tract malignancies. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"92 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710676","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":"Hijacking homeostasis: the brain-body neural circuitry in tumor pathogenesis and emerging therapeutic frontiers","authors":"Yong-Fei Wang, Zi-Kai Dong, Wei-Lin Jin","doi":"10.1186/s12943-025-02396-6","DOIUrl":"https://doi.org/10.1186/s12943-025-02396-6","url":null,"abstract":"Cancer research is undergoing a paradigm shift from solely studying tumor cells to investigating systemic effects of cancer in the tumor macroevironment, with an emphasis on the interactions between host organs and tumors. The theory of homeostasis is an important basis for explaining biological functions from the perspective of the organism. Organic homeostasis relies on brain-body crosstalk through interception, immunoception, nociception and other supervisory processes, guaranteeing normal physiological function. Recent studies reveal that malignant tumors can hijack and exploit the brain and its central-peripheral neuronal networks to disrupt the body's homeostasis. Tumors likely disrupt normal brain-body crosstalk by establishing bidirectional brain-tumor connections. On the contrary, organism utilize these mechanisms to hinder tumorigenesis and progression. Standing at the perspective of brain-body crosstalk also promotes the conceptional evolution of cancer initiation and development, and more importantly, provides additional insight for cancer treatment. In this review, we summarize current knowledge about brain-body crosstalk under tumor-bearing contexts and propose some novel anti-cancer strategies. Brain-body crosstalk participates in the battle between tumors and the organism: The homeostasis of the organism is collectively maintained by interoception, nociception, neuroception, endocriception, metaboception and immunoception. However, in tumor states, tumors hijack the brain-body crosstalk system to exploit these homeostatic mechanisms, thereby constructing a macroenvironment conducive to their survival and progression. While tumors hijack the brain-body crosstalk to reestablish homeostasis, the host organism simultaneously counteracts the tumor through brain-body crosstalk, safeguarding its intrinsic homeostasis from disruption. The brain-body crosstalk between tumors and multiple organs mediated by the HPA axis-driven humoral regulation and the sympathetic and parasympathetic nerves plays a significant role in the battle between tumors and the organism. TME, tumor microenvironment; HPA, hypothalamic-pituitary-adrenal; SAS, sympatho-adrenal system. This figure was created using BioRender ( https://biorender.com/ ). ● Cancer research has experienced a conceptional evolution, from simply regarding cancer as an unorganized cell mass to a newborn organ. Therefore, standing at the perspective of interactions between organs provides novel insight for this area. ● The organic homeostasis is supervised and exerted respectively by interception, nociception, neuroception, endocriception, metaboception and immunoception, which are tightly associated with brain and other components of the nervous system. ● Tumors could hijack the brain-body crosstalk to facilitate their own survival and progression. In turn, the host could utilize this axis to constrain cancer development, and ideally promote cancer elimination. ● According to theory of brain-b","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"52 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701494","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":"PEGylated PLGA nanoparticles: unlocking advanced strategies for cancer therapy.","authors":"Prashant Kesharwani,Vishal Kumar,Khang Wen Goh,Garima Gupta,Abdulrhman Alsayari,Shadma Wahab,Amirhossein Sahebkar","doi":"10.1186/s12943-025-02410-x","DOIUrl":"https://doi.org/10.1186/s12943-025-02410-x","url":null,"abstract":"Poly(lactic-co-glycolic acid) (PLGA) is a widely utilized biodegradable and biocompatible polymer in drug delivery systems, particularly for encapsulating drug molecules with poor solubility and permeability. PLGA nanoparticles, composed of polylactic acid (PLA) and polyglycolic acid (PGA), offer tunable properties such as controlled degradation rates and drug release kinetics. The PEGylation of PLGA nanoparticles results in the formation of a polyethylene glycol (PEG) corona on their surface, which enhances systemic circulation by reducing opsonization and immune system recognition. This extended circulation time increases the likelihood of nanoparticles reaching the target site, a crucial advantage in cancer therapy, as it allows for reduced dosage frequency while improving therapeutic efficacy. Furthermore, surface functionalization with targeting ligands enables selective delivery to specific cells or organs via ligand-receptor interactions, facilitating enhanced cellular uptake and intracellular drug release. This review provides a comprehensive analysis of PEGylated PLGA nanoparticles in cancer diagnosis and therapy, highlighting recent advancements, current challenges, and future perspectives in their clinical translation.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"113 1","pages":"205"},"PeriodicalIF":37.3,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693345","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":"Metabolic reprogramming promotes apoptosis resistance in acute lymphoblastic leukemia through CASP3 lactylation","authors":"Zhi Lin, Fei Long, Jiao Liu, Rui Kang, Daniel J. Klionsky, Guido Kroemer, Daolin Tang, Minghua Yang","doi":"10.1186/s12943-025-02392-w","DOIUrl":"https://doi.org/10.1186/s12943-025-02392-w","url":null,"abstract":"Acute lymphoblastic leukemia (ALL) is characterized by metabolic adaptations that support rapid cell proliferation and resistance to apoptosis. Our study identifies elevated sphingomyelin (SM) as a key metabolic alteration in ALL, contributing to apoptosis resistance via CASP3 (caspase 3) lactylation. Using comprehensive lipidomic analyses of plasma samples from pediatric ALL patients, we observed significantly increased SM concentrations in patients with manifest ALL compared to patients after remission. Mechanistic investigations revealed that elevated SM enhances SLC2A1-dependent glucose uptake and glycolysis, leading to increased lactate production and subsequent CASP3 lactylation on lysine residue 14, which inhibits CASP3 activation and apoptosis. Reduction of intracellular SM levels through SGMS1 knockout or SMPD3 overexpression reduced glycolytic flux and lactate levels, restored CASP3 activity and induced apoptosis in ALL cells. In vivo, SM depletion significantly suppressed ALL progression and prolonged survival in mouse models, highlighting the potential of targeting SM metabolism as a therapeutic strategy. In conclusion, our findings uncover a metabolic pathway linking lipid and glucose metabolism to apoptosis resistance in ALL.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"143 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684658","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":"An immune responsive tumor microenvironment imprints into PBMCs and predicts outcome in advanced pancreatic cancer: lessons from the PREDICT trial","authors":"Anton Lahusen, Manfred P. Lutz, Rui Fang, Martina Kirchner, Sarah Albus, Klaus Kluck, Meinolf Karthaus, Andreas Schwarzer, Gabriele Siegler, Alexander Kleger, Thomas J. Ettrich, Alexander Becher, Sabine Höfling, Jens T. Siveke, Jan Budczies, Andrea Tannapfel, Albrecht Stenzinger, Phyllis Fung-Yi Cheung, Tim Eiseler, Thomas Seufferlein","doi":"10.1186/s12943-025-02406-7","DOIUrl":"https://doi.org/10.1186/s12943-025-02406-7","url":null,"abstract":"Prognosis in advanced pancreatic ductal adenocarcinoma (aPDAC) is particularly poor, only few patients benefit from treatment, and there are few biomarkers. The PREDICT trial examined whether first-line time-to-treatment failure (TTF1) predicts second-line treatment failure (TTF2) in aPDAC patients but found no association. We hypothesized that the tumor immune microenvironment (TiME) could correlate with the outcome in this trial and assessed whether tissue features were reflected in peripheral blood. PREDICT patients received 5-FU/LV plus nanoliposomal irinotecan as second-line treatment. We stratified patients by shortest vs. longest TTF2 and analyzed 20 treatment-naïve tumor tissues samples via transcriptomics and immunohistochemistry. Peripheral blood mononuclear cells (PBMCs) from 82 patients collected prior to second-line therapy underwent flow cytometry and gene expression profiling. A machine learning pipeline integrated PBMC and clinical data to predict second-line outcome including external validation in 30 patients. Long-TTF2 tumors exhibited an immune-active (“hot”) TiME with cytotoxic CXCR3+CD8+-T-cell infiltration. PBMC analysis showed that these immune features were reflected in peripheral blood after one line of treatment. A novel 7-feature PBMC-based model (“TTF2Pred”) accurately predicted TTF2 and overall survival, outperforming clinical or CA19-9 models and was confirmed in an external validation cohort. Long-TTF2 patients exhibited more circulating CXCR3⁺-T-cells and plasmacytoid dendritic cells. Short-TTF2 patients had more platelet-leukocyte aggregates. An immune-active, treatment-naïve TiME predicts a better second-line outcome, and these characteristics imprinted into PBMCs obtained after one line of chemotherapy. We here first describe a minimally invasive, PBMC-based predictor of second-line outcome as a powerful prognostic tool for triaging patients. ClinicalTrials.gov NCT03468335 (registered March 15, 2018).","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"14 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144678034","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":"Primary and secondary metastatic dissemination: multiple routes to cancer-related death","authors":"D. Sparrer, R. Blazquez, F. Keil, S. Einhell, F. Lüke, S. Uderhardt, C. Gerner, C.H.R. Wendl, M. Proescholdt, C. Schulz, A. Kandulski, S. Haferkamp, H.J. Schlitt, T. Bäuerle, K. Franze, R. Mayr, M. Rechenmacher, P. Hau, D. Hirsch, D. Heudobler, K. Evert, T. Pukrop","doi":"10.1186/s12943-025-02389-5","DOIUrl":"https://doi.org/10.1186/s12943-025-02389-5","url":null,"abstract":"Metastatic disease accounts for approximately 80% of cancer-related deaths, typically manifesting as single-organ failure mainly through abdominal, cardiovascular, neurological, or respiratory complications. Despite treating thousands of cancer patients daily worldwide, our understanding of organ-specific metastatic dissemination routes, tissue destruction mechanisms and reasons for organ failures remains limited. As cancer-directed therapies advance, maintaining organ function has emerged as a critical therapeutic goal of care. To develop more effective treatment strategies, a comprehensive understanding of the pathophysiology is essential, particularly regarding secondary and subsequent metastatic waves that lead to extensive macro-metastases and organ failure. Critical distinction between primary metastatic spread and secondary intra-organ dissemination is crucial. In the era of precision oncology, elucidating organ-specific destruction processes and the pathophysiology of metastatic waves is fundamental for advancing patient care. To highlight the emerging goal of care of maintaining organ function, we aligned the metastatic biology, clinical stages, goals of care and therapeutic indications: the Bio Therapeutic Goals of Cancer Care Model.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"17 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677964","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":"NSUN2-mediated cytosine-5 methylation of FSP1 protects acute myeloid leukemia cells from ferroptosis","authors":"Wenle Ye, Yanchun Zhao, Yutong Zhou, Jiansong Huang, Xiao He, Zhixin Ma, Xin Huang, Chao Hu, Fenglin Li, Qing Ling, Huafeng Wang, Hongyan Tong, Jie Sun, Jie Jin","doi":"10.1186/s12943-025-02394-8","DOIUrl":"https://doi.org/10.1186/s12943-025-02394-8","url":null,"abstract":"RNA 5-methylcytosine (m5C), a prevalent epitranscriptomic modification that critically regulates gene expression and cellular homeostasis. While its roles in solid tumors have been increasingly recognized, the functional landscape of m5C in acute myeloid leukemia (AML) remains unexplored. Here, we identified NSUN2, the principal RNA m5C methyltransferase, as a key regulator of AML progression. NSUN2 was aberrantly upregulated in AML patient samples and correlated with poor prognosis. Functional studies demonstrated that NSUN2 promoted leukemic cell proliferation, enhanced tumor growth in xenograft models, and conferred resistance to ferroptosis—a regulated cell death process driven by lipid peroxidation. Mechanistically, NSUN2 catalyzed m⁵C deposition on the 3’UTR of FSP1 (ferroptosis suppressor protein 1) mRNA, facilitating its recognition and stabilization by the m5C reader protein YBX1. This NSUN2-YBX1-FSP1 axis protected AML cells from ferroptotic stress by suppressing lipid peroxidation and oxidative damage. Depletion of NSUN2 or FSP1 induced mitochondrial remodeling, which primed cells for ferroptosis. Reconstitution of wild-type NSUN2 or FSP1 rescued ferroptosis resistance, whereas catalytically inactive NSUN2 (C271A/C321A) or non-functional FSP1 mutants (G2A/E156A) failed to reverse this phenotype. Pharmacological inhibition of NSUN2 with MY-1B or targeting FSP1 with iFSP1 exhibited potent anti-leukemic effects, synergizing robustly with ferroptosis inducers, standard chemotherapy, and the BCL-2 inhibitor venetoclax. Our study unveils NSUN2 and FSP1 as prognostic biomarkers and therapeutic targets in AML. We highlight a novel epitranscriptomic mechanism linking RNA methylation to ferroptosis evasion, providing a dual-strategy approach to overcome AML treatment resistance.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"96 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669702","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":"Application of photodynamic activation of prodrugs combined with phototherapy in tumor treatment.","authors":"Yining Du,Jingyuan Zhao,Shuai Li,Hong Yuan","doi":"10.1186/s12943-025-02404-9","DOIUrl":"https://doi.org/10.1186/s12943-025-02404-9","url":null,"abstract":"The design of prodrugs aims to address the issues of systemic toxicity and poor specificity associated with traditional chemotherapy drugs, thereby improving patient survival rates. However, effectively controlling the activation of prodrugs and further improve the efficacy remains a significant challenge that needs to be addressed. Photodynamic therapy (PDT) is a non-invasive cancer treatment that utilizes photosensitizers (PS) to generate reactive oxygen species (ROS) under light irradiation, selectively killing tumor cells, but PDT still faces challenges such as limited therapeutic efficacy. To address challenge in cancer treatment, light-activated prodrugs have emerged as a promising strategy to achieve precise drug release and activation through light control in terms of time and location. This review explores the classification and mechanisms of light-activated prodrugs, with a focus on covalent and non-covalent photosensitizer-drug conjugates. These approaches enhance targeting, precisely control drug release, and achieve synergistic effects between PDT and chemotherapy. By analyzing these strategies, we highlight their potential in improving PDT efficacy and advancing targeted cancer therapy. Finally, we discuss future directions for designing advanced light-activated prodrug systems, providing new insights for the development of more effective and targeted cancer treatments.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"47 1","pages":"200"},"PeriodicalIF":37.3,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669305","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":"From preneoplastic lesion to heterogenous tumor: recent insights into hepatoblastoma biology and therapeutic opportunities.","authors":"Jun Yang,Andrew M Davidoff,Andrew J Murphy","doi":"10.1186/s12943-025-02405-8","DOIUrl":"https://doi.org/10.1186/s12943-025-02405-8","url":null,"abstract":"Hepatoblastoma is the most common pediatric liver cancer, with the fastest rising incidence among childhood malignancies. Early genomic studies revealed that hepatoblastoma has the lowest mutational burden of any human cancer, however, recent advances in single-cell RNA-seq, multiomics, spatial transcriptomics, and functional genomics screenings have revealed substantial complexity. Diverse cellular subpopulations, divergent WNT signaling, key developmental pathways, and intricate interactions between the tumor cells and tumor immune microenvironment (TME) collectively shape tumor heterogeneity, disease progression, therapeutic responses, and genetic dependencies. Mosaic embryonic loss of heterozygosity (LOH) at chromosome 11p15.5 may be a hepatoblastoma-initiating event, as clonal expansion of 11p15.5 LOH occurs in adjacent normal liver tissue. A cholangiocyte-like subpopulation expresses FGF19, in a SOX4-dependent, paracrine manner, to drive the proliferation of neighboring embryonal hepatoblastoma cells. WNT-signaling dependent MDK promotes the immunosuppressive TME, which impairs immune cell infiltration. The TME may also be driven by islands of erythroblasts, which influence treatment resistance. Plasticity driven by changes in chromatin accessibility enables differentiation transition between hepatocytic and liver progenitor cell types, which is associated with treatment resistance. Here, we review recent findings in pediatric hepatoblastoma cells, tumor-associated cell types, and genetic dependencies that will serve to advance hepatoblastoma therapy. Clinical trial number: Not applicable.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"84 1","pages":"198"},"PeriodicalIF":37.3,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664177","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":"CircABCA1 promotes ccRCC by reprogramming cholesterol metabolism and facilitating M2 macrophage polarization through IGF2BP3-mediated stabilization of SCARB1 mRNA.","authors":"Hao Ning,Yan Jiang,Binbin Li,Junwu Ren,Cong Wang,Ling Wei,Linfei Li,Ai Ran,Zuozhang Li,Jiao Li,Wei Li,Yongquan Wang,Bin Xiao","doi":"10.1186/s12943-025-02398-4","DOIUrl":"https://doi.org/10.1186/s12943-025-02398-4","url":null,"abstract":"BACKGROUNDThe reliance of clear cell renal cell carcinoma (ccRCC) on exogenous cholesterol import implies a metabolic susceptibility. This susceptibility represents a potential avenue that can be exploited as a novel therapeutic approach for ccRCC. Circular RNAs (circRNAs) are emerging regulators in cancer, yet their roles in ccRCC lipid metabolism and tumor microenvironment remodeling remain unclear. This study investigates the tumor-promoting role of circABCA1 in ccRCC cholesterol homeostasis and M2 macrophage polarization.METHODSThe expression levels of circABCA1, IGF2BP3, SCARB1, autophagy-related proteins, and the IGF1R/PI3K/AKT/mTOR and ABCA1/ABCG1 pathways were measured using RT-qPCR and western blot. Untargeted metabolomics, RNA- sequencing, and MS2 RNA-pulldown were conducted to identify targets. Interaction analyses included RNA immunoprecipitation, RNA pull-down, and RNA fluorescence in situ hybridization (FISH) assays. Lipid raft measurements, cholesterol uptake/efflux assays, and lipophagy assessments were performed. A co-culture system between M2 macrophages and ccRCC cells was established. In vivo tumorigenesis and metastasis were evaluated using xenograft models and a hepatic metastasis model. Statistical analyses involved Student's t-tests and ANOVA; significance set at P < 0.05.RESULTSWe identified a novel lipid metabolism-related circRNA, circABCA1, which was upregulated in ccRCC and positively correlated with tumor stage and distant metastasis. Functionally, circABCA1 enhanced the half-life of SCARB1 mRNA by forming a circABCA1-IGF2BP3-SCARB1 mRNA ternary complex, thereby increasing the expression of SCARB1 and consequent cholesterol uptake. Next, elevated cholesterol caused by circABCA1-SCARB1 axis-maintained lipid rafts, initiated IGF1R/PI3K/AKT/mTOR cascade, and protected lipid droplets from being destructed by lipophagy, leading to decreased cholesterol efflux. CircABCA1 facilitated the proliferation and migration of ccRCC in vitro and in vivo in a SCARB1 depended manner. Moreover, we uncovered that circABCA1 facilitated M2 macrophage polarization and subsequent pro-tumor effect by prompting cholesterol uptake of ccRCC from tumor microenvironment in a SCARB1-dependent manner.CONCLUSIONSCircABCA1 plays a crucial role in promoting ccRCC progression by regulating cholesterol metabolism and facilitating M2 macrophage polarization, representing a potential therapeutic target for ccRCC treatment.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"10 1","pages":"199"},"PeriodicalIF":37.3,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664182","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}