Lysine lactylation (Kla), first described in 2019, is an emerging post-translational modification that converts lactate availability into changes in chromatin state and protein function. In cancer, where glycolysis and microenvironmental hypoxia often elevate lactate, lactylation has been linked to transcriptional reprogramming, immune modulation, cellular plasticity, and therapy resistance. Here, we synthesize current evidence across major organ systems to clarify how lactylation is generated, interpreted, and removed, and how it interacts with tumor metabolism and the tumor microenvironment. We summarize enzymatic and non-enzymatic routes to Kla formation, discuss candidate writers, erasers, and readers, and highlight recurring mechanistic patterns spanning histone and non-histone substrates, including regulation of immune-evasive signaling, ferroptosis susceptibility, DNA repair, and stress-adaptation programs. We also integrate translational considerations, outlining druggable nodes within lactate production and transport pathways and within acetyltransferase and deacylase systems, and discuss how lactylation measurements could support patient stratification, pharmacodynamic monitoring, and rational combination strategies. Finally, we identify key open questions that currently limit clinical translation, including site-level causality, cell-type and spatial attribution in patient tissues, assay specificity and quantitative stoichiometry, and the conditions under which lactylation promotes versus restrains tumor progression. Together, this framework aims to guide mechanistic studies and accelerate the development of clinically actionable lactylation-directed interventions.
{"title":"Lactylation in cancer: molecular mechanisms and advances in clinical study.","authors":"Jiale Li,Changfeng Miao,Haijun Guo,Maximo Lin,Rui Chen,Jun Peng,Jiachong Wang,Chunhai Tang,Zigui Chen","doi":"10.1186/s12943-026-02573-1","DOIUrl":"https://doi.org/10.1186/s12943-026-02573-1","url":null,"abstract":"Lysine lactylation (Kla), first described in 2019, is an emerging post-translational modification that converts lactate availability into changes in chromatin state and protein function. In cancer, where glycolysis and microenvironmental hypoxia often elevate lactate, lactylation has been linked to transcriptional reprogramming, immune modulation, cellular plasticity, and therapy resistance. Here, we synthesize current evidence across major organ systems to clarify how lactylation is generated, interpreted, and removed, and how it interacts with tumor metabolism and the tumor microenvironment. We summarize enzymatic and non-enzymatic routes to Kla formation, discuss candidate writers, erasers, and readers, and highlight recurring mechanistic patterns spanning histone and non-histone substrates, including regulation of immune-evasive signaling, ferroptosis susceptibility, DNA repair, and stress-adaptation programs. We also integrate translational considerations, outlining druggable nodes within lactate production and transport pathways and within acetyltransferase and deacylase systems, and discuss how lactylation measurements could support patient stratification, pharmacodynamic monitoring, and rational combination strategies. Finally, we identify key open questions that currently limit clinical translation, including site-level causality, cell-type and spatial attribution in patient tissues, assay specificity and quantitative stoichiometry, and the conditions under which lactylation promotes versus restrains tumor progression. Together, this framework aims to guide mechanistic studies and accelerate the development of clinically actionable lactylation-directed interventions.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"39 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015360","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}
BACKGROUNDOsteosarcoma (OS) is the most prevalent primary cancer of the bone. Metastasis and chemoresistance are the major obstacles to the improvement of OS prognosis, in which N6-methyladenosine (m6A) modification plays an important role, but the exact molecular mechanisms are still unclear.METHODSMeRIP-seq and RNA-seq were conducted on OS and paired adjacent normal tissue samples, which determined CACNA1E as a key m6A-modified molecule. In vitro and in vivo models were established to evaluate the function of CACNA1E on OS growth, metastasis, and methotrexate (MTX) resistance, and to explore the upstream regulators and downstream effectors of CACNA1E.RESULTSCACNA1E exhibited notable m6A hypermethylation and upregulated expression in OS than adjacent normal tissues. CACNA1E knockdown effectively hindered OS growth, lung metastasis, and MTX resistance. METTL3, an m6A "writer" boosted the mRNA stability of CACNA1E through m6A modification, and this process was recognized and enhanced by IGF2BP2, an m6A "reader". WNT7B was identified as a downstream molecule of CACNA1E. CACNA1E facilitated OS progression and MTX resistance by enhancing the non-canonical Wnt/Ca2+ signaling through transcriptionally activating WNT7B. Furthermore, a novel combination treatment of targeted inhibition of CACNA1E with MTX had a synergistic effect on suppressing OS progression.CONCLUSIONSCollectively, our findings uncover that METTL3-mediated m6A modification of CACNA1E contributes to OS progression and chemoresistance through enhancing WNT7B-mediated non-canonical Wnt/Ca2+ signaling. Targeted inhibition of CACNA1E in combination with MTX may be a promising alternative therapeutic strategy for patients with MTX-resistant OS.
{"title":"METTL3-mediated m6A modification of CACNA1E promotes osteosarcoma progression and chemoresistance by enhancing WNT7B-mediated Ca2+ signaling.","authors":"Chaotao Chen,Kai Xiong,Feiyuan Liang,Yanping Zhong,Xiong Qin,Nanchang Huang,Yuqi Fang,Bo Zhu,Jianwen Cheng,Qingjun Wei,Li Zheng,Jinmin Zhao","doi":"10.1186/s12943-025-02553-x","DOIUrl":"https://doi.org/10.1186/s12943-025-02553-x","url":null,"abstract":"BACKGROUNDOsteosarcoma (OS) is the most prevalent primary cancer of the bone. Metastasis and chemoresistance are the major obstacles to the improvement of OS prognosis, in which N6-methyladenosine (m6A) modification plays an important role, but the exact molecular mechanisms are still unclear.METHODSMeRIP-seq and RNA-seq were conducted on OS and paired adjacent normal tissue samples, which determined CACNA1E as a key m6A-modified molecule. In vitro and in vivo models were established to evaluate the function of CACNA1E on OS growth, metastasis, and methotrexate (MTX) resistance, and to explore the upstream regulators and downstream effectors of CACNA1E.RESULTSCACNA1E exhibited notable m6A hypermethylation and upregulated expression in OS than adjacent normal tissues. CACNA1E knockdown effectively hindered OS growth, lung metastasis, and MTX resistance. METTL3, an m6A \"writer\" boosted the mRNA stability of CACNA1E through m6A modification, and this process was recognized and enhanced by IGF2BP2, an m6A \"reader\". WNT7B was identified as a downstream molecule of CACNA1E. CACNA1E facilitated OS progression and MTX resistance by enhancing the non-canonical Wnt/Ca2+ signaling through transcriptionally activating WNT7B. Furthermore, a novel combination treatment of targeted inhibition of CACNA1E with MTX had a synergistic effect on suppressing OS progression.CONCLUSIONSCollectively, our findings uncover that METTL3-mediated m6A modification of CACNA1E contributes to OS progression and chemoresistance through enhancing WNT7B-mediated non-canonical Wnt/Ca2+ signaling. Targeted inhibition of CACNA1E in combination with MTX may be a promising alternative therapeutic strategy for patients with MTX-resistant OS.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"42 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994824","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}
Ferroptosis is a non-apoptotic form of regulated cell death driven by iron dependent lipid peroxidation. It sits at the intersection of several hallmarks of metastatic cancer, including metabolic rewiring, membrane remodeling, epithelial mesenchymal plasticity, immune editing, and adaptation to distant niches. In this review, we integrate biochemical mechanisms with single cell, spatial, and in vivo data to map how ferroptotic pressure changes as tumor cells invade, travel through vessels, extravasate, enter dormancy, and re-awaken to form overt metastases. We highlight that these dynamics are strongly shaped by organ context. Lymph and adipose rich environments buffer lipid peroxidation and favor survival. In contrast, blood circulation increases oxidative load, and brain and liver niches impose distinct constraints on redox balance, iron handling, and lipid repair. We then examine how ferroptosis interfaces with the immune system. Ferroptotic stress can increase tumor antigenicity and danger signaling and thereby promote antitumor responses. The same stress, however, can reprogram monocytes, macrophages, and neutrophils, drive neutrophil extracellular trap formation, and support lipid exchange that weakens effector T cell function. This dual behavior helps explain why ferroptosis can restrict dissemination in some settings yet fuel pro-metastatic inflammation in others. On this mechanistic background, we evaluate therapeutic strategies that aim to exploit ferroptosis related vulnerabilities. These include inhibition of cystine supply or lipid repair pathways, radiosensitization regimens that increase lipid peroxidation, diet drug combinations that rewire sulfur and lipid metabolism, and nanoplatforms that co-deliver ferroptosis triggers with photo or sonodynamic therapies. Clinically, ferroptosis programs are increasingly linked to metastatic organotropism, responses to radiotherapy and immunotherapy, and patient survival, and they are beginning to guide biomarker development and early translational trials. We also discuss practical barriers, such as niche specific resistance circuits, constraints imposed by drug delivery and toxicity, and the scarcity of robust patient level ferroptosis readouts. Methodological advances - including compartment resolved reporters, spatial lipidomics, and circulating signatures of lipid damage - may help address these gaps. Overall, viewing metastasis through the ferroptosis lens reveals actionable vulnerabilities and supports rational radio immunometabolic combinations aimed at durable control of metastatic disease.
{"title":"Ferroptosis and metastasis: molecular checkpoints, microenvironmental dynamics, and therapeutic opportunities.","authors":"Feng Guo,Shi Zong,Xin Zhang,Zhaozhou Ren,Hua Shao,Jingwu Li,Xiaobo Wang,Yu Li,Xiaofeng Wang,Kuanbing Chen","doi":"10.1186/s12943-025-02544-y","DOIUrl":"https://doi.org/10.1186/s12943-025-02544-y","url":null,"abstract":"Ferroptosis is a non-apoptotic form of regulated cell death driven by iron dependent lipid peroxidation. It sits at the intersection of several hallmarks of metastatic cancer, including metabolic rewiring, membrane remodeling, epithelial mesenchymal plasticity, immune editing, and adaptation to distant niches. In this review, we integrate biochemical mechanisms with single cell, spatial, and in vivo data to map how ferroptotic pressure changes as tumor cells invade, travel through vessels, extravasate, enter dormancy, and re-awaken to form overt metastases. We highlight that these dynamics are strongly shaped by organ context. Lymph and adipose rich environments buffer lipid peroxidation and favor survival. In contrast, blood circulation increases oxidative load, and brain and liver niches impose distinct constraints on redox balance, iron handling, and lipid repair. We then examine how ferroptosis interfaces with the immune system. Ferroptotic stress can increase tumor antigenicity and danger signaling and thereby promote antitumor responses. The same stress, however, can reprogram monocytes, macrophages, and neutrophils, drive neutrophil extracellular trap formation, and support lipid exchange that weakens effector T cell function. This dual behavior helps explain why ferroptosis can restrict dissemination in some settings yet fuel pro-metastatic inflammation in others. On this mechanistic background, we evaluate therapeutic strategies that aim to exploit ferroptosis related vulnerabilities. These include inhibition of cystine supply or lipid repair pathways, radiosensitization regimens that increase lipid peroxidation, diet drug combinations that rewire sulfur and lipid metabolism, and nanoplatforms that co-deliver ferroptosis triggers with photo or sonodynamic therapies. Clinically, ferroptosis programs are increasingly linked to metastatic organotropism, responses to radiotherapy and immunotherapy, and patient survival, and they are beginning to guide biomarker development and early translational trials. We also discuss practical barriers, such as niche specific resistance circuits, constraints imposed by drug delivery and toxicity, and the scarcity of robust patient level ferroptosis readouts. Methodological advances - including compartment resolved reporters, spatial lipidomics, and circulating signatures of lipid damage - may help address these gaps. Overall, viewing metastasis through the ferroptosis lens reveals actionable vulnerabilities and supports rational radio immunometabolic combinations aimed at durable control of metastatic disease.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"8 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968348","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}
Pancreatic cancer exhibits a heightened level of autophagy, which supports the survival of cancer cells within the malignant microenvironment. The THUMP domain-containing protein 3 (THUMPD3)/ tRNA Methyltransferase Activator Subunit 11-2 (TRMT112) complex has been identified as a tRNA m2G methyltransferase in mammalian cells, and its functional role remains largely unexplored in pancreatic cancer. In this study, we demonstrate that both THUMPD3 and TRMT112 are upregulated in pancreatic cancer and significantly correlate with poor prognosis for patients. Knockdown of THUMPD3/TRMT112 inhibited pancreatic cancer cell growth in vitro and in vivo. Additionally, THUMPD3/TRMT112 knockdown significantly reduced autophagic flux, suggesting a role for THUMPD3/TRMT112-mediated tRNA m2G modification in promoting pancreatic cancer cell proliferation and maintaining autophagy. Mechanistically, THUMPD3/TRMT112 deficiency suppressed TFEB translation via impaired m2G modification of tRNALeu(CAG), thereby inhibiting pancreatic cancer cell growth and autophagy. In summary, this study has unveiled the crucial role of the THUMPD3/TRMT112 m2G tRNA methyltransferase complex in maintaining pancreatic cancer cell growth and autophagy, presenting a promising target for future precision medicine interventions.
{"title":"tRNA m2G methyltransferase complex THUMPD3-TRMT112 promotes pancreatic cancer progression and autophagy via modulating TFEB translation.","authors":"Wenbin Yuan,Shi Li,Yue Xi,Rui Tian,Yuan Liu,Xingyu Chen,Rui Zhang,Hao Lyu,Shuai Xiao,Dong Guo,Qi Zhang,Wenying Qin,Chaojun Yan,Xing-Zhen Chen,Cefan Zhou,Jingfeng Tang","doi":"10.1186/s12943-025-02540-2","DOIUrl":"https://doi.org/10.1186/s12943-025-02540-2","url":null,"abstract":"Pancreatic cancer exhibits a heightened level of autophagy, which supports the survival of cancer cells within the malignant microenvironment. The THUMP domain-containing protein 3 (THUMPD3)/ tRNA Methyltransferase Activator Subunit 11-2 (TRMT112) complex has been identified as a tRNA m2G methyltransferase in mammalian cells, and its functional role remains largely unexplored in pancreatic cancer. In this study, we demonstrate that both THUMPD3 and TRMT112 are upregulated in pancreatic cancer and significantly correlate with poor prognosis for patients. Knockdown of THUMPD3/TRMT112 inhibited pancreatic cancer cell growth in vitro and in vivo. Additionally, THUMPD3/TRMT112 knockdown significantly reduced autophagic flux, suggesting a role for THUMPD3/TRMT112-mediated tRNA m2G modification in promoting pancreatic cancer cell proliferation and maintaining autophagy. Mechanistically, THUMPD3/TRMT112 deficiency suppressed TFEB translation via impaired m2G modification of tRNALeu(CAG), thereby inhibiting pancreatic cancer cell growth and autophagy. In summary, this study has unveiled the crucial role of the THUMPD3/TRMT112 m2G tRNA methyltransferase complex in maintaining pancreatic cancer cell growth and autophagy, presenting a promising target for future precision medicine interventions.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"30 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961325","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 : 2026-01-13DOI: 10.1186/s12943-025-02566-6
Di Yan,Ying Yu,Chengtong Liang,Zixing Cui,Lei Shi,Guiling Li,Chuanli Ren
Emerging evidence reveals that intratumoral microbial (ITM) communities within the tumor immune microenvironment (TIME) critically influence tumor progression and immunotherapy response. Studies have shown that resident bacteria within tumors, such as Sphingobacterium multivorum, regulate the secretion of chemokines like CCL20 and CXCL8, promoting the infiltration of regulatory T cells (Tregs) and inhibiting the function of cytotoxic T cells (CD8+ T cells)-thereby weakening the efficacy of immune checkpoint inhibitors. Additionally, microbial metabolites may serve as potential biomarkers for predicting sensitivity to immunotherapy. Concurrently, engineered bacteria (e.g., oncolytic mineralizing bacteria) demonstrate significant antitumor effects by activating innate immunity and enhancing antitumor-specific immune responses, providing new strategies to overcome immunotherapy resistance. These findings highlight the dual role of ITM in tumor immune evasion and immunotherapy sensitivity, laying an important theoretical foundation for developing novel immunotherapy strategies targeting tumoral microbiota metabolism.
{"title":"Intratumoral microbiome: the double-edged sword in remodeling cancer immunotherapy.","authors":"Di Yan,Ying Yu,Chengtong Liang,Zixing Cui,Lei Shi,Guiling Li,Chuanli Ren","doi":"10.1186/s12943-025-02566-6","DOIUrl":"https://doi.org/10.1186/s12943-025-02566-6","url":null,"abstract":"Emerging evidence reveals that intratumoral microbial (ITM) communities within the tumor immune microenvironment (TIME) critically influence tumor progression and immunotherapy response. Studies have shown that resident bacteria within tumors, such as Sphingobacterium multivorum, regulate the secretion of chemokines like CCL20 and CXCL8, promoting the infiltration of regulatory T cells (Tregs) and inhibiting the function of cytotoxic T cells (CD8+ T cells)-thereby weakening the efficacy of immune checkpoint inhibitors. Additionally, microbial metabolites may serve as potential biomarkers for predicting sensitivity to immunotherapy. Concurrently, engineered bacteria (e.g., oncolytic mineralizing bacteria) demonstrate significant antitumor effects by activating innate immunity and enhancing antitumor-specific immune responses, providing new strategies to overcome immunotherapy resistance. These findings highlight the dual role of ITM in tumor immune evasion and immunotherapy sensitivity, laying an important theoretical foundation for developing novel immunotherapy strategies targeting tumoral microbiota metabolism.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"4 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961327","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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