This study developed and validated a diagnostic signature comprising five small extracellular vesicle (sEV)-derived long RNAs (ATF4, GRAP2, MCL1, PAK2, PIK3CB) for distinguishing early-stage lung adenocarcinoma (LUAD) from benign pulmonary nodules and assessing prognosis in advanced LUAD. Utilizing a multi-center cohort of 698 participants, researchers employed RNA sequencing and quantitative PCR to analyze plasma sEV RNA profiles. Differentially expressed mRNAs and long intergenic non-coding RNAs (lincRNAs) were identified using LASSO regression to construct a diagnostic model. The signature demonstrated high diagnostic accuracy with an area under the curve (AUC) of 0.971 in the validation cohort and 0.950 in the prospective cohort. It also surpassed low-dose CT sensitivity (95.24% vs. 71.43%), specificity (100% vs. 93.96%), positive predictive value (100% vs. 45.45%) and negative predictive value (99.67% vs. 97.90%) in the prospective cohort. In advanced LUAD patients undergoing chemoradiotherapy or PD-L1 inhibitor therapy, lower expression of these RNAs correlated with improved progression-free survival (PFS; HR = 0.38-0.39). The signature integrates non-invasively detected sEV RNAs to complement LDCT, addressing its high false-positive rate, and offers prognostic insights for personalized treatment strategies. These findings highlight the clinical potential of sEV-derived long RNAs in early LUAD detection and precision oncology.
{"title":"Development and validation of a small extracellular vesicle-derived RNA signature for early diagnosis of lung adenocarcinoma and prognosis in advanced stages.","authors":"Rui Meng,Yanjun Gao,Zheng Peng,Hua Chen,Yida Li,Yu Liu,Lanxiao Shen,Huanle Pan,Liangcheng Zheng,Dezhi Cheng,Xiaoming Lin,Wenjie Sun,Congying Xie","doi":"10.1186/s12943-025-02524-2","DOIUrl":"https://doi.org/10.1186/s12943-025-02524-2","url":null,"abstract":"This study developed and validated a diagnostic signature comprising five small extracellular vesicle (sEV)-derived long RNAs (ATF4, GRAP2, MCL1, PAK2, PIK3CB) for distinguishing early-stage lung adenocarcinoma (LUAD) from benign pulmonary nodules and assessing prognosis in advanced LUAD. Utilizing a multi-center cohort of 698 participants, researchers employed RNA sequencing and quantitative PCR to analyze plasma sEV RNA profiles. Differentially expressed mRNAs and long intergenic non-coding RNAs (lincRNAs) were identified using LASSO regression to construct a diagnostic model. The signature demonstrated high diagnostic accuracy with an area under the curve (AUC) of 0.971 in the validation cohort and 0.950 in the prospective cohort. It also surpassed low-dose CT sensitivity (95.24% vs. 71.43%), specificity (100% vs. 93.96%), positive predictive value (100% vs. 45.45%) and negative predictive value (99.67% vs. 97.90%) in the prospective cohort. In advanced LUAD patients undergoing chemoradiotherapy or PD-L1 inhibitor therapy, lower expression of these RNAs correlated with improved progression-free survival (PFS; HR = 0.38-0.39). The signature integrates non-invasively detected sEV RNAs to complement LDCT, addressing its high false-positive rate, and offers prognostic insights for personalized treatment strategies. These findings highlight the clinical potential of sEV-derived long RNAs in early LUAD detection and precision oncology.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"20 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657026","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}
Pub Date : 2025-12-03DOI: 10.1186/s12943-025-02521-5
Hengshuo Liu,Xingyu Xiong,Weizhen Zhu,Sheng Wang,Weichao Huang,Guoqing Zhu,Hang Xu,Lu Yang
Gut microbiota-derived metabolites are emerging as systemic "remote immunoregulators" that shape tumor immunity across tissues. Integrating evidence across short-chain fatty acids, tryptophan derivatives, secondary bile acids, polyamines and other metabolites, we advance a metabolite-immune pathway-cancer framework that links receptor-mediated signaling, epigenetic remodeling and metabolic reprogramming to context-dependent, bidirectional immune effects. Importantly, in addition to the g protein-coupled receptor / aryl hydrocarbon receptor pathway, the selected microbial small molecule metabolites are the true T-cell receptor ligands of unconventional T cells, directly shaping the tissue resident immune and tumor microenvironment, supplementing the receptor signaling and epigenetic programs in our framework. We synthesize how these metabolites recalibrate the tumor immune microenvironment-modulating antigen presentation, T-cell effector fitness and exhaustion, regulatory T-cell activity, and myeloid polarization-and why the same metabolite can either potentiate immune surveillance or entrench immunosuppression depending on ligand-receptor pairing, dose and tissue niche. We compare tumor-type specific patterns (e.g., colorectal, liver, lung, breast and prostate cancers) to highlight common circuits and organ-restricted idiosyncrasies. Methodologically, we outline how single-cell and spatial multi-omics, imaging mass spectrometry and functional biosensors now enable co-registration of metabolite exposure with immune-cell states in human tumors, providing an actionable basis for biomarker discovery. Given ongoing debate about signals attributed to intratumoral microbiota in low-biomass tumor tissues, we foreground quantifiable, spatially mappable and pharmacologically tractable metabolite-receptor pathways, using microbe-associated molecular patterns / translocation as comparators to judge when chemical signals should be prioritized as intervention targets. Finally, we evaluate precision intervention avenues-including fecal microbiota transplantation, rational bacterial consortia, engineered microbes and nanoparticle-enabled metabolite delivery-and propose stratification rules that pair metabolite/receptor signatures with fit-for-purpose delivery. Together, mapping tissue-specific metabolite-immune circuits and embedding them in robust biomarker frameworks may convert microbial metabolites from correlative markers into therapeutic targets and tools, improving the efficacy and durability of cancer immunotherapy.
{"title":"Gut microbial metabolites in cancer immunomodulation.","authors":"Hengshuo Liu,Xingyu Xiong,Weizhen Zhu,Sheng Wang,Weichao Huang,Guoqing Zhu,Hang Xu,Lu Yang","doi":"10.1186/s12943-025-02521-5","DOIUrl":"https://doi.org/10.1186/s12943-025-02521-5","url":null,"abstract":"Gut microbiota-derived metabolites are emerging as systemic \"remote immunoregulators\" that shape tumor immunity across tissues. Integrating evidence across short-chain fatty acids, tryptophan derivatives, secondary bile acids, polyamines and other metabolites, we advance a metabolite-immune pathway-cancer framework that links receptor-mediated signaling, epigenetic remodeling and metabolic reprogramming to context-dependent, bidirectional immune effects. Importantly, in addition to the g protein-coupled receptor / aryl hydrocarbon receptor pathway, the selected microbial small molecule metabolites are the true T-cell receptor ligands of unconventional T cells, directly shaping the tissue resident immune and tumor microenvironment, supplementing the receptor signaling and epigenetic programs in our framework. We synthesize how these metabolites recalibrate the tumor immune microenvironment-modulating antigen presentation, T-cell effector fitness and exhaustion, regulatory T-cell activity, and myeloid polarization-and why the same metabolite can either potentiate immune surveillance or entrench immunosuppression depending on ligand-receptor pairing, dose and tissue niche. We compare tumor-type specific patterns (e.g., colorectal, liver, lung, breast and prostate cancers) to highlight common circuits and organ-restricted idiosyncrasies. Methodologically, we outline how single-cell and spatial multi-omics, imaging mass spectrometry and functional biosensors now enable co-registration of metabolite exposure with immune-cell states in human tumors, providing an actionable basis for biomarker discovery. Given ongoing debate about signals attributed to intratumoral microbiota in low-biomass tumor tissues, we foreground quantifiable, spatially mappable and pharmacologically tractable metabolite-receptor pathways, using microbe-associated molecular patterns / translocation as comparators to judge when chemical signals should be prioritized as intervention targets. Finally, we evaluate precision intervention avenues-including fecal microbiota transplantation, rational bacterial consortia, engineered microbes and nanoparticle-enabled metabolite delivery-and propose stratification rules that pair metabolite/receptor signatures with fit-for-purpose delivery. Together, mapping tissue-specific metabolite-immune circuits and embedding them in robust biomarker frameworks may convert microbial metabolites from correlative markers into therapeutic targets and tools, improving the efficacy and durability of cancer immunotherapy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"1 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145663941","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}
Pub Date : 2025-12-03DOI: 10.1186/s12943-025-02539-9
Zaira Ianniello, Huimei Lu, Elias Quijano, Daniel A Colón-Ríos, Madison Rackear, Venu Bommireddy, Dale L Ludwig, Zhiyuan Shen, Peter M Glazer
{"title":"Correction: Harnessing ExDNA for precision Exatecan delivery in cancer: a novel antibody-drug conjugate approach.","authors":"Zaira Ianniello, Huimei Lu, Elias Quijano, Daniel A Colón-Ríos, Madison Rackear, Venu Bommireddy, Dale L Ludwig, Zhiyuan Shen, Peter M Glazer","doi":"10.1186/s12943-025-02539-9","DOIUrl":"10.1186/s12943-025-02539-9","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"24 1","pages":"304"},"PeriodicalIF":33.9,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12673787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145669026","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}
Pub Date : 2025-12-02DOI: 10.1186/s12943-025-02514-4
Mingchao Xie,Miljenka Vuko,Shashank Saran,Siyu Liu,Andrew G Chambers,Hana Baakza,Helen K Angell,Felicia Ng,Carl M Gay,Robert J Cardnell,Felix J Segerer,Alma Andoni,Jaime Rodriguez-Canales,Paul M Waring,Markus Schick,J Carl Barrett,Lauren A Byers,Giulia Fabbri
BACKGROUNDGreater understanding of differential therapeutic sensitivity, specifically to immunotherapy, in small-cell lung cancer (SCLC) is required.METHODSWe explored SCLC heterogeneity through integrated molecular characterization of tumor tissue samples from 159 treatment-naive patients, utilizing genetic, epigenetic, transcriptional, and proteomic profiling, immunohistochemistry staining for multiple biologically relevant markers including transcriptional subtype-defining proteins, and spatial immune profiling using multiplex immunofluorescence.RESULTSMulti-omics analysis confirmed high heterogeneity across/within neuroendocrine and non-neuroendocrine subtypes. Methylomics analysis identified four methylome clusters that may enhance subtype prediction, prognosis, and longitudinal monitoring of subtype evolution. Immunohistochemistry analysis showed high MHC-I expression in non-neuroendocrine subtypes, which have greatest potential benefit from adding immunotherapy to chemotherapy; high DLL3 expression associated with neuroendocrine subtypes and an immune-cold tumor microenvironment. Multiplex immunofluorescence demonstrated associations of MHC-I with spatial arrangement and phenotypic features of immune cells in the tumor microenvironment of high-MHC-I-expressing SCLC, providing mechanistic rationale for MHC-I as a potential biomarker of immunotherapy response.CONCLUSIONSThis multimodal profiling analysis provides further insights into the biologic complexity of SCLC and highlights potential therapeutic vulnerabilities of distinct disease subtypes.
{"title":"Multi-omic profiling provides insights into the heterogeneity, microenvironmental features, and biomarker landscape of small-cell lung cancer.","authors":"Mingchao Xie,Miljenka Vuko,Shashank Saran,Siyu Liu,Andrew G Chambers,Hana Baakza,Helen K Angell,Felicia Ng,Carl M Gay,Robert J Cardnell,Felix J Segerer,Alma Andoni,Jaime Rodriguez-Canales,Paul M Waring,Markus Schick,J Carl Barrett,Lauren A Byers,Giulia Fabbri","doi":"10.1186/s12943-025-02514-4","DOIUrl":"https://doi.org/10.1186/s12943-025-02514-4","url":null,"abstract":"BACKGROUNDGreater understanding of differential therapeutic sensitivity, specifically to immunotherapy, in small-cell lung cancer (SCLC) is required.METHODSWe explored SCLC heterogeneity through integrated molecular characterization of tumor tissue samples from 159 treatment-naive patients, utilizing genetic, epigenetic, transcriptional, and proteomic profiling, immunohistochemistry staining for multiple biologically relevant markers including transcriptional subtype-defining proteins, and spatial immune profiling using multiplex immunofluorescence.RESULTSMulti-omics analysis confirmed high heterogeneity across/within neuroendocrine and non-neuroendocrine subtypes. Methylomics analysis identified four methylome clusters that may enhance subtype prediction, prognosis, and longitudinal monitoring of subtype evolution. Immunohistochemistry analysis showed high MHC-I expression in non-neuroendocrine subtypes, which have greatest potential benefit from adding immunotherapy to chemotherapy; high DLL3 expression associated with neuroendocrine subtypes and an immune-cold tumor microenvironment. Multiplex immunofluorescence demonstrated associations of MHC-I with spatial arrangement and phenotypic features of immune cells in the tumor microenvironment of high-MHC-I-expressing SCLC, providing mechanistic rationale for MHC-I as a potential biomarker of immunotherapy response.CONCLUSIONSThis multimodal profiling analysis provides further insights into the biologic complexity of SCLC and highlights potential therapeutic vulnerabilities of distinct disease subtypes.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"119 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657046","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}
Pub Date : 2025-12-01DOI: 10.1186/s12943-025-02520-6
Yansheng Wu, Hao Li, Kai Yue, Chao Jing, Yuansheng Duan
Ferroptosis is a form of cell death, distinct from apoptosis, necrosis and autophagy. It is a novel programmed cell death (PCD) triggered by iron accumulation and peroxidation associated with intracellular iron metabolism disorders. Since its naming in 2012, ferroptosis has garnered increasing attention for its role in human diseases, particularly in tumor formation, progression and therapy. Numerous studies have demonstrated that ferroptosis plays a crucial role in killing tumor cells, inhibiting tumor proliferation and metastasis and reversing therapy resistance. Consequently, targeted induction of ferroptosis in tumor cells holds promise as a novel antitumor therapeutic strategy.
{"title":"Ferroptosis in cancer: metabolism, mechanisms and therapeutic prospects.","authors":"Yansheng Wu, Hao Li, Kai Yue, Chao Jing, Yuansheng Duan","doi":"10.1186/s12943-025-02520-6","DOIUrl":"10.1186/s12943-025-02520-6","url":null,"abstract":"<p><p>Ferroptosis is a form of cell death, distinct from apoptosis, necrosis and autophagy. It is a novel programmed cell death (PCD) triggered by iron accumulation and peroxidation associated with intracellular iron metabolism disorders. Since its naming in 2012, ferroptosis has garnered increasing attention for its role in human diseases, particularly in tumor formation, progression and therapy. Numerous studies have demonstrated that ferroptosis plays a crucial role in killing tumor cells, inhibiting tumor proliferation and metastasis and reversing therapy resistance. Consequently, targeted induction of ferroptosis in tumor cells holds promise as a novel antitumor therapeutic strategy.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"24 1","pages":"303"},"PeriodicalIF":33.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12667084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145655016","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}
Pub Date : 2025-11-29DOI: 10.1186/s12943-025-02522-4
Do Young Hyeon, Dowoon Nam, Hye-Jin Shin, Juhee Jeong, Eunsoo Jung, Soo Young Cho, Dong Hoon Shin, Ja-Lok Ku, Hye Jung Baek, Chong Woo Yoo, Eun-Kyung Hong, Myong Cheol Lim, Sang-Jin Lee, Young-Ki Bae, Jong Kwang Kim, Jingi Bae, Wonyoung Choi, Su-Jin Kim, Seunghoon Back, Chaewon Kang, Inamul Hasan Madar, Hokeun Kim, Suhwan Kim, Duk Ki Kim, Jihyung Kang, Geon Woo Park, Ki Seok Park, Yourae Shin, Sang Soo Kim, Keehoon Jung, Daehee Hwang, Sang-Won Lee, Joo-Young Kim
{"title":"Correction: Proteogenomic characterization of molecular and cellular targets for treatment‑resistant subtypes in locally advanced cervical cancers.","authors":"Do Young Hyeon, Dowoon Nam, Hye-Jin Shin, Juhee Jeong, Eunsoo Jung, Soo Young Cho, Dong Hoon Shin, Ja-Lok Ku, Hye Jung Baek, Chong Woo Yoo, Eun-Kyung Hong, Myong Cheol Lim, Sang-Jin Lee, Young-Ki Bae, Jong Kwang Kim, Jingi Bae, Wonyoung Choi, Su-Jin Kim, Seunghoon Back, Chaewon Kang, Inamul Hasan Madar, Hokeun Kim, Suhwan Kim, Duk Ki Kim, Jihyung Kang, Geon Woo Park, Ki Seok Park, Yourae Shin, Sang Soo Kim, Keehoon Jung, Daehee Hwang, Sang-Won Lee, Joo-Young Kim","doi":"10.1186/s12943-025-02522-4","DOIUrl":"10.1186/s12943-025-02522-4","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"24 1","pages":"301"},"PeriodicalIF":33.9,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12664262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636186","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}
Pub Date : 2025-11-29DOI: 10.1186/s12943-025-02535-z
Ariel Km Chow, Nathan Sm Cheng, Colin Sc Lam, Lui Ng, Sunny Km Wong, Timothy Mh Wan, Johnny Hw Man, Alvin Hk Cheung, Thomas Cc Yau, Jensen Tc Poon, Wai-Lun Law, Roberta Wc Pang
{"title":"Retraction Note: Preclinical analysis of the anti-tumor and anti-metastatic effects of Raf265 on colon cancer cells and CD26<sup>+</sup> cancer stem cells in colorectal carcinoma.","authors":"Ariel Km Chow, Nathan Sm Cheng, Colin Sc Lam, Lui Ng, Sunny Km Wong, Timothy Mh Wan, Johnny Hw Man, Alvin Hk Cheung, Thomas Cc Yau, Jensen Tc Poon, Wai-Lun Law, Roberta Wc Pang","doi":"10.1186/s12943-025-02535-z","DOIUrl":"10.1186/s12943-025-02535-z","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"24 1","pages":"302"},"PeriodicalIF":33.9,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12664263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145636137","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}
Pub Date : 2025-11-28DOI: 10.1186/s12943-025-02518-0
Alicia K Fleming Martinez,Heike R Döppler,Ryan Argo,Ligia I Bastea,Brandy H Edenfield,Irene Espositio,Peter Storz
{"title":"Downregulation of Sod2 increases atypical flat lesions and dysplasia to advance pancreatic ductal adenocarcinoma.","authors":"Alicia K Fleming Martinez,Heike R Döppler,Ryan Argo,Ligia I Bastea,Brandy H Edenfield,Irene Espositio,Peter Storz","doi":"10.1186/s12943-025-02518-0","DOIUrl":"https://doi.org/10.1186/s12943-025-02518-0","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"90 1","pages":"300"},"PeriodicalIF":37.3,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145613345","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}
Pub Date : 2025-11-27DOI: 10.1186/s12943-025-02497-2
Hong Zheng,Yan-Qi Li,Xiao Lu,Jiao Zhang,Sha-Sha Yu,Xu-Feng Deng,Xiao-Bing Liu,Man-Yuan Li,Yi Cao,Qian Chen,Yuan Qiu,Quan-Xing Liu,Dong Zhou,Ji-Gang Dai
Most persistent ground glass nodules (GGNs) are eventually diagnosed as early-stage lung adenocarcinoma (LUAD). Delving into the molecular underpinnings of malignant transformation of GGNs will aid in the development of preventive and therapeutic strategies to interrupt the occurrence and progression of early-stage LUAD. Macrophages (Macs) are critical in the formation of immunosuppressive tumor microenvironment (TME). However, its role in triggering the advancement of early-stage LUAD with mixed ground glass nodule (mGGN) is yet to be clarified. Utilizing scRNA-seq analysis on normal lung tissues, ground glass regions, and solid regions of mGGNs, complemented by multicolor immunohistochemistry (mIHC) and flow cytometry, we found an increase and peri-tumoral aggregation of immunosuppressive SPP1+ alveolar Macs and monocyte-derived Macs (Mo-Macs), with a particular emphasis on the Mo-Macs. This accumulation at the tumor margin could obstruct the penetration of immune cells into the tumor's core, thereby promoting the malignant transformation of GGNs. SPP1+ Macs not only display a senescent phenotype but also harbor the potential capacity to foster tumor metastasis and angiogenesis. Clinical data from LUAD tissue array and TCGA-LUAD database revealed a positive association between the tumoral SPP1+ Macs percentage and poor prognosis. Furthermore, SPP1+ Macs could reshape the TME into an immunosuppressive state through interactions with other immune cells. In vitro and in vivo assays revealed SPP1 knockout inhibited the immunosuppressive polarization and senescence of Macs, reversed the immunosuppressive status of TME and reduced the growth of LUAD xenograft tumors. Our findings propose an emerging therapeutic strategy aimed at suppressing SPP1+ Macs, which could potentially decelerate or halt the malignant conversion of GGNs to early-stage LUAD.
{"title":"Senescent SPP1+ macrophages remodel the tumor microenvironment and promote the progression of early-stage lung adenocarcinoma featured with mixed ground glass nodule.","authors":"Hong Zheng,Yan-Qi Li,Xiao Lu,Jiao Zhang,Sha-Sha Yu,Xu-Feng Deng,Xiao-Bing Liu,Man-Yuan Li,Yi Cao,Qian Chen,Yuan Qiu,Quan-Xing Liu,Dong Zhou,Ji-Gang Dai","doi":"10.1186/s12943-025-02497-2","DOIUrl":"https://doi.org/10.1186/s12943-025-02497-2","url":null,"abstract":"Most persistent ground glass nodules (GGNs) are eventually diagnosed as early-stage lung adenocarcinoma (LUAD). Delving into the molecular underpinnings of malignant transformation of GGNs will aid in the development of preventive and therapeutic strategies to interrupt the occurrence and progression of early-stage LUAD. Macrophages (Macs) are critical in the formation of immunosuppressive tumor microenvironment (TME). However, its role in triggering the advancement of early-stage LUAD with mixed ground glass nodule (mGGN) is yet to be clarified. Utilizing scRNA-seq analysis on normal lung tissues, ground glass regions, and solid regions of mGGNs, complemented by multicolor immunohistochemistry (mIHC) and flow cytometry, we found an increase and peri-tumoral aggregation of immunosuppressive SPP1+ alveolar Macs and monocyte-derived Macs (Mo-Macs), with a particular emphasis on the Mo-Macs. This accumulation at the tumor margin could obstruct the penetration of immune cells into the tumor's core, thereby promoting the malignant transformation of GGNs. SPP1+ Macs not only display a senescent phenotype but also harbor the potential capacity to foster tumor metastasis and angiogenesis. Clinical data from LUAD tissue array and TCGA-LUAD database revealed a positive association between the tumoral SPP1+ Macs percentage and poor prognosis. Furthermore, SPP1+ Macs could reshape the TME into an immunosuppressive state through interactions with other immune cells. In vitro and in vivo assays revealed SPP1 knockout inhibited the immunosuppressive polarization and senescence of Macs, reversed the immunosuppressive status of TME and reduced the growth of LUAD xenograft tumors. Our findings propose an emerging therapeutic strategy aimed at suppressing SPP1+ Macs, which could potentially decelerate or halt the malignant conversion of GGNs to early-stage LUAD.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"70 1","pages":"298"},"PeriodicalIF":37.3,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145613207","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}
CIC::DUX4 sarcoma (CDS) is a highly aggressive malignancy with limited therapeutic options. Here, we present a doxycycline-inducible CIC::DUX4 chimeric mouse model and a cancer line derived from it, imChCDS, that faithfully recapitulates the molecular, histological, and immunological features of human CDS. We demonstrate that CIC::DUX4 expression alone is sufficient to drive tumorigenesis in permissive lineages of soft connective tissues. The imChCDS cell line retains the transcriptional footprint of its mesenchymal cell of origin, develops metastatic tumors in immunocompetent hosts, and exhibits a clear dependency on the P300/CBP transcriptional co-activators. Notably, we identify CIC::DUX4/P300/CBP-mediated suppression of MHC class I (MHCI) as a key mechanism of CDS immune evasion. Genetical inactivation of CIC::DUX4 or pharmacological inhibition of P300/CBP induces cancer cell cycle arrest, restores MHCI expression, and triggers robust anti-tumor immune responses, thereby transforming the immunologically "cold" CDS microenvironment into a "hot" one and driving tumor regression. Together, these models offer a versatile and physiologically relevant platform to investigate CDS pathogenesis, unravel immune evasion mechanisms, and evaluate emerging therapeutic strategies, including those targeting CIC::DUX4/P300/CBP oncogenic axis.
{"title":"Modeling CIC::DUX4 sarcoma reveals oncogene-mediated MHCI-dependent immune evasion.","authors":"Ajay Ram Vachanaram,Erdong Wei,Ana Mitanoska,William Bassett,Michael Kyba,Darko Bosnakovski","doi":"10.1186/s12943-025-02485-6","DOIUrl":"https://doi.org/10.1186/s12943-025-02485-6","url":null,"abstract":"CIC::DUX4 sarcoma (CDS) is a highly aggressive malignancy with limited therapeutic options. Here, we present a doxycycline-inducible CIC::DUX4 chimeric mouse model and a cancer line derived from it, imChCDS, that faithfully recapitulates the molecular, histological, and immunological features of human CDS. We demonstrate that CIC::DUX4 expression alone is sufficient to drive tumorigenesis in permissive lineages of soft connective tissues. The imChCDS cell line retains the transcriptional footprint of its mesenchymal cell of origin, develops metastatic tumors in immunocompetent hosts, and exhibits a clear dependency on the P300/CBP transcriptional co-activators. Notably, we identify CIC::DUX4/P300/CBP-mediated suppression of MHC class I (MHCI) as a key mechanism of CDS immune evasion. Genetical inactivation of CIC::DUX4 or pharmacological inhibition of P300/CBP induces cancer cell cycle arrest, restores MHCI expression, and triggers robust anti-tumor immune responses, thereby transforming the immunologically \"cold\" CDS microenvironment into a \"hot\" one and driving tumor regression. Together, these models offer a versatile and physiologically relevant platform to investigate CDS pathogenesis, unravel immune evasion mechanisms, and evaluate emerging therapeutic strategies, including those targeting CIC::DUX4/P300/CBP oncogenic axis.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"14 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145609911","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}
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