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}
BACKGROUNDAberrant RHOA activation drives tumor progression, yet regulatory mechanisms beyond genetic mutations remain poorly defined. Lactylation, a lactate-derived post-translational modification, links metabolic reprogramming to oncogenesis, but its functional mimicry of genetic mutations is unexplored. This study investigates RHOA lactylation at oncogenic hotspots and its role as an "epi-mutation" system.METHODSRHOA lactylation were identified by pan-lysine lactylation (Kla) antibody-based mass spectrometry. Site-specific lactylation was achieved using an orthogonal Mb-Pyl Kla-RS/Pyl-tRNA pair to incorporate lactyl-lysine at K118/K162 in recombinant RHOA, validated by immunoblotting and fluorescence. Molecular dynamics simulations (AlphaFold 3, BIOVIA DS) analyzed GTPase activity and hydrogen-bond networks. RHOA activity was assessed via ROCK2-RBD pull-down and GTPase assays. Ubiquitination and protein stability were examined using cycloheximide chase and K48/K63-ubiquitin mutants. In vitro lactylation/delactylation assays with PCAF/HDAC3 defined enzyme specificity. In vitro/in vivo functional studies used migration/invasion assays and xenograft models. Clinical relevance was evaluated in breast cancer tissues and survival databases.RESULTSWe identify lactylation of RHOA at oncogenic mutation hotspots K118 and K162, mediated by the lactate-PCAF/HDAC3 axis. Mechanistically, K118 lactylation constitutively activates RHOA by impairing intrinsic GTPase activity, whereas K162 lactylation stabilizes RHOA protein by competitively antagonizing protein ubiquitination, with USP9X further enhancing stability through deubiquitination. Functionally, RHOA lactylation promotes tumor cell migration, invasion and metastasis. Clinically, RHOA lactylation is elevated in breast tumors versus adjacent tissues. Notably, targeting lactate production (LDHA inhibitor: sodium oxamate) synergized with RHOA-pathway inhibition (ROCK inhibitor: Y-27632) to suppress tumor progression. By employing a site-specific lactylation system, we further identify that lactylation mimics oncogenic mutations by enhancing both RHOA activity and stability, thus proposing that lactylation at mutation-prone sites represents a reversible "epi-mutation" system that recapitulates genetic mutation effects.CONCLUSIONSRHOA lactylation at K118 (activation) and K162 (stabilization) orchestrated by the PCAF/HDAC3 enzymatic axis, enables constitutive oncogenic signaling to fuel tumor progression. Crucially, we redefine that lactylation at mutation-prone sites functions as a reversible "epi-mutation" system, where metabolic modification dynamically recapitulates oncogenic mutation effects, challenging the genetic/epigenetic dichotomy in oncology and revealing dual targeting of lactylation and canonical RHOA pathways as a potential therapeutic strategy.
{"title":"RHOA lactylation at oncogenic hotspots promotes oncogenic activity and protein stabilization.","authors":"Chenglong Ma,Ruocen Liao,Xingyu Chen,Qianhua Cao,Xinyue Deng,Zhijun Dai,Chenfang Dong","doi":"10.1186/s12943-025-02511-7","DOIUrl":"https://doi.org/10.1186/s12943-025-02511-7","url":null,"abstract":"BACKGROUNDAberrant RHOA activation drives tumor progression, yet regulatory mechanisms beyond genetic mutations remain poorly defined. Lactylation, a lactate-derived post-translational modification, links metabolic reprogramming to oncogenesis, but its functional mimicry of genetic mutations is unexplored. This study investigates RHOA lactylation at oncogenic hotspots and its role as an \"epi-mutation\" system.METHODSRHOA lactylation were identified by pan-lysine lactylation (Kla) antibody-based mass spectrometry. Site-specific lactylation was achieved using an orthogonal Mb-Pyl Kla-RS/Pyl-tRNA pair to incorporate lactyl-lysine at K118/K162 in recombinant RHOA, validated by immunoblotting and fluorescence. Molecular dynamics simulations (AlphaFold 3, BIOVIA DS) analyzed GTPase activity and hydrogen-bond networks. RHOA activity was assessed via ROCK2-RBD pull-down and GTPase assays. Ubiquitination and protein stability were examined using cycloheximide chase and K48/K63-ubiquitin mutants. In vitro lactylation/delactylation assays with PCAF/HDAC3 defined enzyme specificity. In vitro/in vivo functional studies used migration/invasion assays and xenograft models. Clinical relevance was evaluated in breast cancer tissues and survival databases.RESULTSWe identify lactylation of RHOA at oncogenic mutation hotspots K118 and K162, mediated by the lactate-PCAF/HDAC3 axis. Mechanistically, K118 lactylation constitutively activates RHOA by impairing intrinsic GTPase activity, whereas K162 lactylation stabilizes RHOA protein by competitively antagonizing protein ubiquitination, with USP9X further enhancing stability through deubiquitination. Functionally, RHOA lactylation promotes tumor cell migration, invasion and metastasis. Clinically, RHOA lactylation is elevated in breast tumors versus adjacent tissues. Notably, targeting lactate production (LDHA inhibitor: sodium oxamate) synergized with RHOA-pathway inhibition (ROCK inhibitor: Y-27632) to suppress tumor progression. By employing a site-specific lactylation system, we further identify that lactylation mimics oncogenic mutations by enhancing both RHOA activity and stability, thus proposing that lactylation at mutation-prone sites represents a reversible \"epi-mutation\" system that recapitulates genetic mutation effects.CONCLUSIONSRHOA lactylation at K118 (activation) and K162 (stabilization) orchestrated by the PCAF/HDAC3 enzymatic axis, enables constitutive oncogenic signaling to fuel tumor progression. Crucially, we redefine that lactylation at mutation-prone sites functions as a reversible \"epi-mutation\" system, where metabolic modification dynamically recapitulates oncogenic mutation effects, challenging the genetic/epigenetic dichotomy in oncology and revealing dual targeting of lactylation and canonical RHOA pathways as a potential therapeutic strategy.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"29 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599784","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 : 2025-11-25DOI: 10.1186/s12943-025-02507-3
Marine Fidelle,Hui Chen,Léa Montégut,David Boulate,Pamela Abdayem,Magalie Martineau,Tatiana Kuznetsova,Carlijn M van der Aalst,Harry J de Koning,Laurence Zitvogel,Guido Kroemer
BACKGROUNDAcyl-coenzyme A binding protein (ACBP), encoded by the diazepam binding inhibitor (DBI) gene, is a tissue stress hormone the circulating concentrations of which increase with age, obesity and cardiometabolic risk factors. Elevated plasma ACBP/DBI levels have recently been associated with future cardiovascular and cancer risk, particularly lung cancer (LC), independent of smoking status.METHODSTo validate ACBP/DBI as a biomarker of LC risk, we analyzed plasma samples from four independent cohorts within the PREVALUNG EU consortium: healthy volunteers, the FLEMENGHO cohort of smokers at cardiovascular risk, the ROBINSCA cohort of smokers at risk of cardiovascular disease (CVD) who later developed LC, and the PREVALUNG cohort of smokers with manifest CVD. ACBP/DBI concentrations were quantified using the Olink proximity extension assay, benchmarked against ELISA and Somascan platforms.RESULTSAcross cohorts, individuals who subsequently developed LC exhibited higher baseline ACBP/DBI levels than cancer-free controls. In smokers at cardiovascular risk but without manifest CVD, ACBP/DBI discriminated future LC cases with an AUC-ROC of 0.68 (unadjusted) and 0.73 (adjusted for age, sex, BMI and smoking). Elevated ACBP/DBI levels predicted LC occurrence over more than a decade of follow-up. In contrast, among smokers with established CVD, ACBP/DBI levels were uniformly high regardless of cancer outcome.CONCLUSIONSThese findings independently validate ACBP/DBI as a circulating biomarker of future LC development in at-risk individuals. Clinically, ACBP/DBI quantification could refine risk-adapted lung cancer screening strategies, guiding the frequency of low-dose CT scans and identifying candidates for preventive interventions, including potential ACBP/DBI-neutralizing therapies.
{"title":"Increased plasma concentrations of acyl-coenzyme A binding protein (ACBP) predict future lung cancer development in smokers at risk of cardiovascular disease.","authors":"Marine Fidelle,Hui Chen,Léa Montégut,David Boulate,Pamela Abdayem,Magalie Martineau,Tatiana Kuznetsova,Carlijn M van der Aalst,Harry J de Koning,Laurence Zitvogel,Guido Kroemer","doi":"10.1186/s12943-025-02507-3","DOIUrl":"https://doi.org/10.1186/s12943-025-02507-3","url":null,"abstract":"BACKGROUNDAcyl-coenzyme A binding protein (ACBP), encoded by the diazepam binding inhibitor (DBI) gene, is a tissue stress hormone the circulating concentrations of which increase with age, obesity and cardiometabolic risk factors. Elevated plasma ACBP/DBI levels have recently been associated with future cardiovascular and cancer risk, particularly lung cancer (LC), independent of smoking status.METHODSTo validate ACBP/DBI as a biomarker of LC risk, we analyzed plasma samples from four independent cohorts within the PREVALUNG EU consortium: healthy volunteers, the FLEMENGHO cohort of smokers at cardiovascular risk, the ROBINSCA cohort of smokers at risk of cardiovascular disease (CVD) who later developed LC, and the PREVALUNG cohort of smokers with manifest CVD. ACBP/DBI concentrations were quantified using the Olink proximity extension assay, benchmarked against ELISA and Somascan platforms.RESULTSAcross cohorts, individuals who subsequently developed LC exhibited higher baseline ACBP/DBI levels than cancer-free controls. In smokers at cardiovascular risk but without manifest CVD, ACBP/DBI discriminated future LC cases with an AUC-ROC of 0.68 (unadjusted) and 0.73 (adjusted for age, sex, BMI and smoking). Elevated ACBP/DBI levels predicted LC occurrence over more than a decade of follow-up. In contrast, among smokers with established CVD, ACBP/DBI levels were uniformly high regardless of cancer outcome.CONCLUSIONSThese findings independently validate ACBP/DBI as a circulating biomarker of future LC development in at-risk individuals. Clinically, ACBP/DBI quantification could refine risk-adapted lung cancer screening strategies, guiding the frequency of low-dose CT scans and identifying candidates for preventive interventions, including potential ACBP/DBI-neutralizing therapies.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"20 1","pages":"296"},"PeriodicalIF":37.3,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599785","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 : 2025-11-25DOI: 10.1186/s12943-025-02506-4
Ali Alishvandi,Cena Aram,Farzaneh Faraji Shahrivar,Prashant Kesharwani,Amirhossein Sahebkar
Pyroptosis, a caspase-dependent form of inflammatory programmed cell death, is driven by inflammasome activation and gasdermin-mediated membrane pore formation. Its immunogenic nature has attracted increasing attention in oncology, particularly for overcoming therapeutic challenges such as chemoresistance, radiotherapy failure, and immune checkpoint blockade non-responsiveness. By promoting the release of pro-inflammatory cytokines and damage-associated molecular patterns (DAMPs), pyroptosis can enhance antitumor immunity and reshape the tumor microenvironment (TME). However, sustained or dysregulated pyroptosis can lead to chronic inflammation, radiotherapy-induced tissue injury, and tumorigenesis, making it a double-edged sword. Emerging evidence shows that pyroptosis exhibits cancer-type-specific roles, depending on the molecular context and the extent of activation. Therefore, understanding the molecular regulators, tumor-specific signaling, and temporal dynamics of pyroptosis is essential for its therapeutic modulation. This review comprehensively outlines the dual roles of pyroptosis in cancer progression and treatment, discusses its molecular mechanisms, and highlights recent strategies to harness or suppress pyroptosis for therapeutic gain. Targeting pyroptosis offers a promising, yet complex, avenue for immune-enhancing cancer therapies.
{"title":"Pyroptosis in cancer therapy: a double-edged sword for immune activation and tumor progression.","authors":"Ali Alishvandi,Cena Aram,Farzaneh Faraji Shahrivar,Prashant Kesharwani,Amirhossein Sahebkar","doi":"10.1186/s12943-025-02506-4","DOIUrl":"https://doi.org/10.1186/s12943-025-02506-4","url":null,"abstract":"Pyroptosis, a caspase-dependent form of inflammatory programmed cell death, is driven by inflammasome activation and gasdermin-mediated membrane pore formation. Its immunogenic nature has attracted increasing attention in oncology, particularly for overcoming therapeutic challenges such as chemoresistance, radiotherapy failure, and immune checkpoint blockade non-responsiveness. By promoting the release of pro-inflammatory cytokines and damage-associated molecular patterns (DAMPs), pyroptosis can enhance antitumor immunity and reshape the tumor microenvironment (TME). However, sustained or dysregulated pyroptosis can lead to chronic inflammation, radiotherapy-induced tissue injury, and tumorigenesis, making it a double-edged sword. Emerging evidence shows that pyroptosis exhibits cancer-type-specific roles, depending on the molecular context and the extent of activation. Therefore, understanding the molecular regulators, tumor-specific signaling, and temporal dynamics of pyroptosis is essential for its therapeutic modulation. This review comprehensively outlines the dual roles of pyroptosis in cancer progression and treatment, discusses its molecular mechanisms, and highlights recent strategies to harness or suppress pyroptosis for therapeutic gain. Targeting pyroptosis offers a promising, yet complex, avenue for immune-enhancing cancer therapies.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"116 1","pages":"297"},"PeriodicalIF":37.3,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145599565","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}
Paclitaxel plus ramucirumab (PTX + RAM) is a widely used second-line treatment for advanced gastric cancer, yet no validated biomarkers exist to predict therapeutic response. Identifying non-invasive predictors could enable patient stratification and optimize outcomes. We conducted a prospective observational multicenter study (IVY trial; NCT06490055) enrolling 115 patients with advanced gastric cancer treated with PTX + RAM. Serum was collected prior to the initiation of treatment. Small RNA sequencing identified differentially expressed exosomal microRNAs (exo-miRNAs) in patients with controlled disease versus those with progressive disease. Machine learning and logistic regression were employed to construct a predictive model, which was subsequently validated using quantitative real-time polymerase chain reaction (qRT-PCR) in the entire cohort. Ten candidate exo-miRNAs were initially discovered, and a five-miRNA panel (miR-10a-5p, miR-25-5p, miR-125a-5p, miR-139-5p, and miR-450a-5p) was selected via stepwise elimination. This 5-exo-miRNA model achieved high accuracy in distinguishing controlled disease patients from progressive disease patients (AUC = 0.84). When combined with body mass index (BMI), the composite model (EXEMPLAR) demonstrated enhanced predictive performance (AUC = 0.87). High-risk patients exhibited significantly shorter progression-free survival (PFS: median, 1.9 vs. 4.2 months, p = 0.019) and overall survival (OS: median, 1.1 vs. 1.7 years, p < 0.001). Decision curve analysis confirmed the clinical benefit of the model. A nomogram was developed to facilitate personalized risk assessment. This study identifies and validates a novel 5-exo-miRNA panel for predicting response to second-line PTX plus RAM therapy in gastric cancer. The combined exosomal signature and BMI risk model provides a clinically applicable, non-invasive tool for personalized treatment selection.
{"title":"A machine-learning powered liquid biopsy predicts response to paclitaxel plus ramucirumab in advanced gastric cancer: results from the prospective IVY trial","authors":"Katsutoshi Shoda, Caiming Xu, Takeshi Nagasaka, Daisuke Ichikawa, Ajay Goel","doi":"10.1186/s12943-025-02526-0","DOIUrl":"https://doi.org/10.1186/s12943-025-02526-0","url":null,"abstract":"Paclitaxel plus ramucirumab (PTX + RAM) is a widely used second-line treatment for advanced gastric cancer, yet no validated biomarkers exist to predict therapeutic response. Identifying non-invasive predictors could enable patient stratification and optimize outcomes. We conducted a prospective observational multicenter study (IVY trial; NCT06490055) enrolling 115 patients with advanced gastric cancer treated with PTX + RAM. Serum was collected prior to the initiation of treatment. Small RNA sequencing identified differentially expressed exosomal microRNAs (exo-miRNAs) in patients with controlled disease versus those with progressive disease. Machine learning and logistic regression were employed to construct a predictive model, which was subsequently validated using quantitative real-time polymerase chain reaction (qRT-PCR) in the entire cohort. Ten candidate exo-miRNAs were initially discovered, and a five-miRNA panel (miR-10a-5p, miR-25-5p, miR-125a-5p, miR-139-5p, and miR-450a-5p) was selected via stepwise elimination. This 5-exo-miRNA model achieved high accuracy in distinguishing controlled disease patients from progressive disease patients (AUC = 0.84). When combined with body mass index (BMI), the composite model (EXEMPLAR) demonstrated enhanced predictive performance (AUC = 0.87). High-risk patients exhibited significantly shorter progression-free survival (PFS: median, 1.9 vs. 4.2 months, p = 0.019) and overall survival (OS: median, 1.1 vs. 1.7 years, p < 0.001). Decision curve analysis confirmed the clinical benefit of the model. A nomogram was developed to facilitate personalized risk assessment. This study identifies and validates a novel 5-exo-miRNA panel for predicting response to second-line PTX plus RAM therapy in gastric cancer. The combined exosomal signature and BMI risk model provides a clinically applicable, non-invasive tool for personalized treatment selection.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"96 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145568002","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 : 2025-11-22DOI: 10.1186/s12943-025-02529-x
Xiao-Xiao Huang, Cheng-Ke Xie, Yi-Chao Mo, Wei Li, Yong-Ding Wu, Zhi-Yuan Li, Hao-Xiang Zhang, Ge Li, Long Jin, Xin-Quan Lin, Jian-Fei Hu, Yin-Hao Chen, Hong-Yi Lin, Shun-Cang Zhu, Jin-Peng Lu, Hou-Juan Zhu, Wan-Wan Wang, Yi Huang, Zu-Wei Wang, Long Huang, Dan-Feng Wang, Yi-Feng Tian, Cheng-Yu Liao, Shi Chen
Cuproptosis, a newly identified form of cell death, is closely linked to copper homeostasis and protein lipoylation. Using a multi-omics approach, we firstly reveal that SERPINB3 confers cuproptosis resistance in pancreatic cancer and functions as a theranostic biomarker. Mechanistically, SERPINB3 inhibits FDX1 transcription by activating the MAPK signaling pathway, thereby conferring cuproptosis resistance. We further demonstrated that SERPINB3 directly interacts with MEK1, impeding its chaperone-mediated autophagic degradation, which ultimately leads to sustained activation of the MAPK signaling pathway. Additionally, we found that SERPINB3 promotes pancreatic cancer immune evasion by upregulating PD-L1 expression on tumor cells. This phenomenon motivated the development of a triple-combination strategy consisting of MAPK inhibition, cuproptosis induction, and αPD-1 therapy for pancreatic cancer patients with high SERPINB3 expression. To this end, we further developed a metal-organic framework (MOF) loaded with both copper ions and MEK inhibitor, which significantly triggers tumor-specific cuproptosis and enhances antitumor immunity. In summary, SERPINB3 serves as a predictive biomarker to inform therapeutic strategies targeting cuproptosis, thereby establishing a novel paradigm for cancer immunotherapy that integrates metal biology, targeted therapy, and immune modulation.
{"title":"Targeting SERPINB3–MAPK axis-mediated cuproptosis resistance enhances the response to antitumor immunotherapy","authors":"Xiao-Xiao Huang, Cheng-Ke Xie, Yi-Chao Mo, Wei Li, Yong-Ding Wu, Zhi-Yuan Li, Hao-Xiang Zhang, Ge Li, Long Jin, Xin-Quan Lin, Jian-Fei Hu, Yin-Hao Chen, Hong-Yi Lin, Shun-Cang Zhu, Jin-Peng Lu, Hou-Juan Zhu, Wan-Wan Wang, Yi Huang, Zu-Wei Wang, Long Huang, Dan-Feng Wang, Yi-Feng Tian, Cheng-Yu Liao, Shi Chen","doi":"10.1186/s12943-025-02529-x","DOIUrl":"https://doi.org/10.1186/s12943-025-02529-x","url":null,"abstract":"Cuproptosis, a newly identified form of cell death, is closely linked to copper homeostasis and protein lipoylation. Using a multi-omics approach, we firstly reveal that SERPINB3 confers cuproptosis resistance in pancreatic cancer and functions as a theranostic biomarker. Mechanistically, SERPINB3 inhibits FDX1 transcription by activating the MAPK signaling pathway, thereby conferring cuproptosis resistance. We further demonstrated that SERPINB3 directly interacts with MEK1, impeding its chaperone-mediated autophagic degradation, which ultimately leads to sustained activation of the MAPK signaling pathway. Additionally, we found that SERPINB3 promotes pancreatic cancer immune evasion by upregulating PD-L1 expression on tumor cells. This phenomenon motivated the development of a triple-combination strategy consisting of MAPK inhibition, cuproptosis induction, and αPD-1 therapy for pancreatic cancer patients with high SERPINB3 expression. To this end, we further developed a metal-organic framework (MOF) loaded with both copper ions and MEK inhibitor, which significantly triggers tumor-specific cuproptosis and enhances antitumor immunity. In summary, SERPINB3 serves as a predictive biomarker to inform therapeutic strategies targeting cuproptosis, thereby establishing a novel paradigm for cancer immunotherapy that integrates metal biology, targeted therapy, and immune modulation. ","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"149 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145567905","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}
Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited therapeutic options and poor prognosis. Although the single-nucleotide polymorphism rs3810151 (p.Val94Ala) in ZNF526 has been identified as a breast cancer susceptibility locus, the functional role and mechanistic basis of ZNF526 in TNBC remain unknown. In this study, we observed that ZNF526 is highly expressed in TNBC, and its elevated expression correlates with worse clinical outcomes. Functional assays revealed that ZNF526 overexpression promotes TNBC cell growth, whereas its knockdown suppresses tumor growth. Mechanistically, we discovered that ZNF526 activates SHMT1 expression, which subsequently enhances flux through the serine-glycine-one-carbon (SGOC) metabolic pathway. This metabolic activation increases glutathione (GSH) production, reduces reactive oxygen species (ROS) levels, and strengthens cellular antioxidant defenses, thereby facilitating TNBC progression. Our findings reveal ZNF526 as a novel regulator of redox balance in TNBC through SHMT1-mediated metabolic control, positioning it as a potential therapeutic target for TNBC.
{"title":"ZNF526 drives tumor growth by enhancing SHMT1-dependent serine metabolism and antioxidant capability in TNBC","authors":"Wenxing Qin, Lujing Shao, Qi Li, Dan Zhang, Xinyan Jia, Chunyan Dong","doi":"10.1186/s12943-025-02503-7","DOIUrl":"https://doi.org/10.1186/s12943-025-02503-7","url":null,"abstract":"Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited therapeutic options and poor prognosis. Although the single-nucleotide polymorphism rs3810151 (p.Val94Ala) in ZNF526 has been identified as a breast cancer susceptibility locus, the functional role and mechanistic basis of ZNF526 in TNBC remain unknown. In this study, we observed that ZNF526 is highly expressed in TNBC, and its elevated expression correlates with worse clinical outcomes. Functional assays revealed that ZNF526 overexpression promotes TNBC cell growth, whereas its knockdown suppresses tumor growth. Mechanistically, we discovered that ZNF526 activates SHMT1 expression, which subsequently enhances flux through the serine-glycine-one-carbon (SGOC) metabolic pathway. This metabolic activation increases glutathione (GSH) production, reduces reactive oxygen species (ROS) levels, and strengthens cellular antioxidant defenses, thereby facilitating TNBC progression. Our findings reveal ZNF526 as a novel regulator of redox balance in TNBC through SHMT1-mediated metabolic control, positioning it as a potential therapeutic target for TNBC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"126 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554112","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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