Pub Date : 2025-12-08DOI: 10.1016/j.canlet.2025.218209
Nathalie Babl , Florian Voll , Agnieszka Martowicz , Christina Bruss , Marianna Maddaloni , Christian Schmidl , Michael Rehli , Stefan Loipfinger , Nicholas Strieder , Claudia Gebhard , Petra Hoffmann , Sukh M. Singh , Ada Sala-Hojman , Roberta Ferretti , Carina Matos , Malte Simon , Christina Brummer , Annette Schnell , Joshua Hofbauer , Sonja-Maria Decking , Marina Kreutz
Paradoxically, immune cell infiltration correlates with worse prognosis in renal cell carcinoma (RCC) patients, with tumor-associated myeloid cells playing a key role in tumor progression. However, little is known about factors driving their polarization. Here, we investigated the link between RCC-related glycolysis, hypoxia-inducible factor (HIF)1α-associated myeloid inflammation, and patient prognosis.
TCGA data revealed a strong correlation between the expression of monocarboxylate transporter 4 (MCT4), the myeloid marker CD14 and patient survival in ccRCC patients. scRNAseq data confirmed high MCT4 expression in both tumor and myeloid cells, suggesting lactate transport. In vitro analyses proved lactate uptake by CD14+ monocytes, which stabilized HIF1α and induced an MDSC-like, HLA-DR low phenotype. In line, the HIF1α-stabilizing drug Roxadustat increased the number of CD14+ HLA-DR low cells. Lactate uptake also increased protein lactylation.
To further investigate the interplay between RCC tumor and myeloid cells, we established a 3D spheroid co-culture model and analyzed the effects of MCT inhibitors. This 3D model reflected tumor-myeloid cell interactions, as spheroid-infiltrating myeloid cells exhibited spontaneous IL-6 secretion comparable to patient-derived RCC cultures. Inhibition of lactate secretion reduced lactate and IL-6 secretion while increasing CD14+ HLA-DR+ cells. These findings were validated in patient-derived RCC cultures treated with anti-glycolytic drugs.
Our data dissect the intratumoral network of RCC and show that tumor-derived lactate promotes a pro-tumorigenic myeloid phenotype with low MHC-II but high immune-checkpoint, LOX-1 and S100A8/9 expression. Blocking MCT disrupts this interplay, offering a promising strategy to re-educate tumor-associated myeloid cells and enhance tumor immune surveillance.
{"title":"Lactic acid promotes an MDSC-like phenotype via HIF1α stabilization with impact on prognosis in renal cell carcinoma","authors":"Nathalie Babl , Florian Voll , Agnieszka Martowicz , Christina Bruss , Marianna Maddaloni , Christian Schmidl , Michael Rehli , Stefan Loipfinger , Nicholas Strieder , Claudia Gebhard , Petra Hoffmann , Sukh M. Singh , Ada Sala-Hojman , Roberta Ferretti , Carina Matos , Malte Simon , Christina Brummer , Annette Schnell , Joshua Hofbauer , Sonja-Maria Decking , Marina Kreutz","doi":"10.1016/j.canlet.2025.218209","DOIUrl":"10.1016/j.canlet.2025.218209","url":null,"abstract":"<div><div>Paradoxically, immune cell infiltration correlates with worse prognosis in renal cell carcinoma (RCC) patients, with tumor-associated myeloid cells playing a key role in tumor progression. However, little is known about factors driving their polarization. Here, we investigated the link between RCC-related glycolysis, hypoxia-inducible factor (HIF)1α-associated myeloid inflammation, and patient prognosis.</div><div>TCGA data revealed a strong correlation between the expression of monocarboxylate transporter 4 (MCT4), the myeloid marker CD14 and patient survival in ccRCC patients. scRNAseq data confirmed high MCT4 expression in both tumor and myeloid cells, suggesting lactate transport. <em>In vitro</em> analyses proved lactate uptake by CD14<sup>+</sup> monocytes, which stabilized HIF1α and induced an MDSC-like, HLA-DR low phenotype. In line, the HIF1α-stabilizing drug Roxadustat increased the number of CD14<sup>+</sup> HLA-DR low cells. Lactate uptake also increased protein lactylation.</div><div>To further investigate the interplay between RCC tumor and myeloid cells, we established a 3D spheroid co-culture model and analyzed the effects of MCT inhibitors. This 3D model reflected tumor-myeloid cell interactions, as spheroid-infiltrating myeloid cells exhibited spontaneous IL-6 secretion comparable to patient-derived RCC cultures. Inhibition of lactate secretion reduced lactate and IL-6 secretion while increasing CD14<sup>+</sup> HLA-DR<sup>+</sup> cells. These findings were validated in patient-derived RCC cultures treated with anti-glycolytic drugs.</div><div>Our data dissect the intratumoral network of RCC and show that tumor-derived lactate promotes a pro-tumorigenic myeloid phenotype with low MHC-II but high immune-checkpoint, LOX-1 and S100A8/9 expression. Blocking MCT disrupts this interplay, offering a promising strategy to re-educate tumor-associated myeloid cells and enhance tumor immune surveillance.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218209"},"PeriodicalIF":10.1,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145721005","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 : 2025-12-08DOI: 10.1016/j.canlet.2025.218208
Xuechuan Li , Ke Liu , Lin Li , Siyuan Yan , Yue Yang , Yang Yang , Jiahua Yang , Lu Zou , Weijian Li , Guoqiang Li , Mao Yang , Liguo Liu , Ziyi Wang , Yajun Geng , Wei Gong , Yingbin Liu , Xiangsong Wu
Reprogrammed cellular metabolism plays a critical role in the development and progression of various cancers. However, the mechanisms by which these metabolic changes drive malignancy in gallbladder cancer (GBC) remain unclear. In this study, we identified significant alterations in branched-chain amino acid (BCAA) metabolism in GBC through comprehensive transcriptomic and metabolic analyses. Reduced activity of the BCAA catabolic enzymes ACADS, ACADSB, and BCKDHA was associated with poor prognosis in GBC patients. Dietary reduction of BCAAs in mouse model of GBC significantly slowed tumor growth. The lncRNA LPAL2 was found to correlate with the expression of BCAA catabolic enzymes. In vivo and in vitro assays demonstrated that LPAL2 inhibited GBC cell proliferation, downregulated intracellular BCAA levels, and suppressed mTORC1 activation. Furthermore, LPAL2 and ACADS were identified as independent prognostic factors for survival. Mechanically, IGF2BP1 maintaining LPAL2 stability through methylation. Additionally, LPAL2 decreased YBX1 stability by promoting its ubiquitination-mediated degradation, while YBX1 inhibited the transcription of certain BCAA catabolic enzymes through binding to their promoters. In summary, the LPAL2-YBX1 interaction regulates BCAA metabolism to influence GBC cell proliferation, which could be targeted for therapeutic interventions in GBC treatment.
{"title":"Loss of branched-chain amino acid (BCAA) metabolism mediated by IGF2BP1-LPAL2-YBX1 interaction promotes malignancy in gallbladder cancer","authors":"Xuechuan Li , Ke Liu , Lin Li , Siyuan Yan , Yue Yang , Yang Yang , Jiahua Yang , Lu Zou , Weijian Li , Guoqiang Li , Mao Yang , Liguo Liu , Ziyi Wang , Yajun Geng , Wei Gong , Yingbin Liu , Xiangsong Wu","doi":"10.1016/j.canlet.2025.218208","DOIUrl":"10.1016/j.canlet.2025.218208","url":null,"abstract":"<div><div>Reprogrammed cellular metabolism plays a critical role in the development and progression of various cancers. However, the mechanisms by which these metabolic changes drive malignancy in gallbladder cancer (GBC) remain unclear. In this study, we identified significant alterations in branched-chain amino acid (BCAA) metabolism in GBC through comprehensive transcriptomic and metabolic analyses. Reduced activity of the BCAA catabolic enzymes ACADS, ACADSB, and BCKDHA was associated with poor prognosis in GBC patients. Dietary reduction of BCAAs in mouse model of GBC significantly slowed tumor growth. The lncRNA LPAL2 was found to correlate with the expression of BCAA catabolic enzymes. In vivo and in vitro assays demonstrated that LPAL2 inhibited GBC cell proliferation, downregulated intracellular BCAA levels, and suppressed mTORC1 activation. Furthermore, LPAL2 and ACADS were identified as independent prognostic factors for survival. Mechanically, IGF2BP1 maintaining LPAL2 stability through methylation. Additionally, LPAL2 decreased YBX1 stability by promoting its ubiquitination-mediated degradation, while YBX1 inhibited the transcription of certain BCAA catabolic enzymes through binding to their promoters. In summary, the LPAL2-YBX1 interaction regulates BCAA metabolism to influence GBC cell proliferation, which could be targeted for therapeutic interventions in GBC treatment.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218208"},"PeriodicalIF":10.1,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145721024","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 : 2025-12-08DOI: 10.1016/j.canlet.2025.218212
Shi-Yu Zhang , De-Zhen Guo , Xin Zhang , Zhu-Jun Gu , Ling Aye , Jia-Yan Yan , Kai Zhu , Xiu-Tao Fu , Shuang-Tao Zhou , Da-Wei Jin , Guo-Huan Yang , Qi-Man Sun , Yi-Feng He , Kang Song , Xiao-Wu Huang , Wei-Ren Liu , Zhen-Bin Ding , Ying-Hong Shi , Xin-Rong Yang , Jia Fan , Ao Huang
Minimal residual disease (MRD) is proposed to drive early recurrence of hepatocellular carcinoma (HCC) after curative treatment, and patients with MRD may benefit from adjuvant treatment. We applied a customized targeted deep sequencing (TDS) to profile tumor genomic alterations in HCC patients undergoing liver transplantation (LT) or hepatectomy, and evaluated their associations with MRD status, recurrence risk, and adjuvant lenvatinib response across multiple independent cohorts. TDS revealed MRD-associated genomic patterns, including increased mutation burden and frequent alterations in TP53 and switch/sucrose non-fermentable (SWI/SNF) genes. Alterations in TP53 and SWI/SNF genes were consistently associated with higher early recurrence rates (48.5 % vs 30.0 %, P = 0.026 for TP53; 56.2 % vs 34.0 %, P = 0.024 for the SWI/SNF genes) and shorter recurrence-free survival (12.2 vs 34.6 months, P = 0.026 for TP53; 9.3 vs 18.6 months, P = 0.018 for the SWI/SNF genes) in the LT cohort, as well as the hepatectomy cohort. Multivariate analysis confirmed these alterations as independent risk factors for MRD. Integrative analysis demonstrated that TP53- and SWI/SNF-altered HCC represent clinically and biologically distinct phenotypes, differing in etiology, differentiation status, mutation burden, and transcriptomic subtypes: TP53 alterations correlated with an epithelial-mesenchymal transition-related subtype, while the SWI/SNF genes alterations related to a MYC-activated subtype. Notably, patients harboring TP53 alterations derived clinical benefit from adjuvant lenvatinib following curative surgery. In conclusion, TDS enables effective identification of MRD-associated genomic alterations and stratifies HCC patients who may benefit from adjuvant lenvatinib, providing a molecular basis for personalized postoperative management.
{"title":"Application of targeted deep sequencing for management of hepatocellular carcinoma in a real-world setting: prediction of MRD and adjuvant lenvatinib response","authors":"Shi-Yu Zhang , De-Zhen Guo , Xin Zhang , Zhu-Jun Gu , Ling Aye , Jia-Yan Yan , Kai Zhu , Xiu-Tao Fu , Shuang-Tao Zhou , Da-Wei Jin , Guo-Huan Yang , Qi-Man Sun , Yi-Feng He , Kang Song , Xiao-Wu Huang , Wei-Ren Liu , Zhen-Bin Ding , Ying-Hong Shi , Xin-Rong Yang , Jia Fan , Ao Huang","doi":"10.1016/j.canlet.2025.218212","DOIUrl":"10.1016/j.canlet.2025.218212","url":null,"abstract":"<div><div>Minimal residual disease (MRD) is proposed to drive early recurrence of hepatocellular carcinoma (HCC) after curative treatment, and patients with MRD may benefit from adjuvant treatment. We applied a customized targeted deep sequencing (TDS) to profile tumor genomic alterations in HCC patients undergoing liver transplantation (LT) or hepatectomy, and evaluated their associations with MRD status, recurrence risk, and adjuvant lenvatinib response across multiple independent cohorts. TDS revealed MRD-associated genomic patterns, including increased mutation burden and frequent alterations in <em>TP53</em> and switch/sucrose non-fermentable (SWI/SNF) genes. Alterations in <em>TP53</em> and SWI/SNF genes were consistently associated with higher early recurrence rates (48.5 % vs 30.0 %, <em>P</em> = 0.026 for <em>TP53</em>; 56.2 % vs 34.0 %, <em>P</em> = 0.024 for the SWI/SNF genes) and shorter recurrence-free survival (12.2 vs 34.6 months, <em>P</em> = 0.026 for <em>TP53</em>; 9.3 vs 18.6 months, <em>P</em> = 0.018 for the SWI/SNF genes) in the LT cohort, as well as the hepatectomy cohort. Multivariate analysis confirmed these alterations as independent risk factors for MRD. Integrative analysis demonstrated that <em>TP53</em>- and SWI/SNF-altered HCC represent clinically and biologically distinct phenotypes, differing in etiology, differentiation status, mutation burden, and transcriptomic subtypes: <em>TP53</em> alterations correlated with an epithelial-mesenchymal transition-related subtype, while the SWI/SNF genes alterations related to a MYC-activated subtype. Notably, patients harboring <em>TP53</em> alterations derived clinical benefit from adjuvant lenvatinib following curative surgery. In conclusion, TDS enables effective identification of MRD-associated genomic alterations and stratifies HCC patients who may benefit from adjuvant lenvatinib, providing a molecular basis for personalized postoperative management.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218212"},"PeriodicalIF":10.1,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145721046","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 : 2025-12-06DOI: 10.1016/j.canlet.2025.218175
Yiqing You , Lan Wei , Meng Dai , Guozhi Zhao , Kun Fan , Tingting Dang , Haoli Sun , Liang Zhang , Qian Li , Mengxin Sun , Xiaolu Li , Xiran He , Shiyu Yang , Tao Zeng , Jiafeng Tang , Yan Zhang
Immunotherapy represents a pivotal strategy for triple-negative breast cancer (TNBC), yet its efficacy is constrained by the immunosuppressive tumor microenvironment (TME). In this study, we demonstrate that bone morphogenetic protein-9 (BMP9) inhibits tumor growth and reprograms the immune TME in orthotopic TNBC models, primarily by attenuating regulatory T cells (Tregs) infiltration. Tregs depletion abrogates si-BMP9-mediated tumor promotion. Mechanistically, BMP9 suppresses CCL2 expression in an exocrine-independent manner to restrict Tregs recruitment. We identify DNA-dependent protein kinase catalytic subunit (PRKDC) as a BMP9-binding transcriptional regulator. The interaction between PRKDC and BMP9 directly impedes CCL2 transcriptional activation by suppressing PRKDC phosphorylation and indirectly suppresses CCL2 expression via NF-κB pathway remodeling. Critically, BMP9 modulation and CCL2 targeting potentiates immunotherapy efficacy without observable toxicity. Our study unveils the BMP9-PRKDC-CCL2 axis as a master regulatory node for TNBC-Tregs crosstalk, providing a strategy to overcome immunotherapy resistance in TNBC.
免疫治疗是治疗三阴性乳腺癌（TNBC）的关键策略，但其疗效受到免疫抑制肿瘤微环境（TME）的限制。在这项研究中，我们证明骨形态发生蛋白9 （bone morphogenetic protein-9, BMP9）主要通过减弱调节性T细胞（regulatory T cells, Tregs）浸润来抑制原位TNBC模型中的肿瘤生长并重新编程免疫TME。Tregs的缺失消除了bmp9介导的肿瘤抑制。从机制上讲，BMP9以外分泌无关的方式抑制CCL2的表达，从而限制Tregs的募集。我们鉴定出dna依赖性蛋白激酶催化亚基（PRKDC）是一种结合bmp9的转录调节因子。PRKDC与BMP9的相互作用通过抑制PRKDC磷酸化直接抑制CCL2的转录激活，并通过NF-κB通路重塑间接抑制CCL2的表达。关键的是，BMP9调节和CCL2靶向增强了免疫治疗效果，而没有明显的毒性。我们的研究揭示了BMP9-PRKDC-CCL2轴作为TNBC- tregs串扰的主调控节点，提供了克服TNBC免疫治疗耐药的策略。
{"title":"BMP9 potentiates immunotherapy in triple-negative breast cancer by suppressing Tregs infiltration via the PRKDC-CCL2 axis","authors":"Yiqing You , Lan Wei , Meng Dai , Guozhi Zhao , Kun Fan , Tingting Dang , Haoli Sun , Liang Zhang , Qian Li , Mengxin Sun , Xiaolu Li , Xiran He , Shiyu Yang , Tao Zeng , Jiafeng Tang , Yan Zhang","doi":"10.1016/j.canlet.2025.218175","DOIUrl":"10.1016/j.canlet.2025.218175","url":null,"abstract":"<div><div>Immunotherapy represents a pivotal strategy for triple-negative breast cancer (TNBC), yet its efficacy is constrained by the immunosuppressive tumor microenvironment (TME). In this study, we demonstrate that bone morphogenetic protein-9 (BMP9) inhibits tumor growth and reprograms the immune TME in orthotopic TNBC models, primarily by attenuating regulatory T cells (Tregs) infiltration. Tregs depletion abrogates si-BMP9-mediated tumor promotion. Mechanistically, BMP9 suppresses CCL2 expression in an exocrine-independent manner to restrict Tregs recruitment. We identify DNA-dependent protein kinase catalytic subunit (PRKDC) as a BMP9-binding transcriptional regulator. The interaction between PRKDC and BMP9 directly impedes CCL2 transcriptional activation by suppressing PRKDC phosphorylation and indirectly suppresses CCL2 expression via NF-κB pathway remodeling. Critically, BMP9 modulation and CCL2 targeting potentiates immunotherapy efficacy without observable toxicity. Our study unveils the BMP9-PRKDC-CCL2 axis as a master regulatory node for TNBC-Tregs crosstalk, providing a strategy to overcome immunotherapy resistance in TNBC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218175"},"PeriodicalIF":10.1,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707391","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 : 2025-12-05DOI: 10.1016/j.canlet.2025.218188
Lina Song , Jialiang Cai , Guiqi Zhu , Peiling Zhang , Shiping Chen , Bing Quan , Junxian Du , Yufan Cai , Lele Song , Jian Zhou , Jia Fan , Tao Li , Lei Yu , Zhi Dai
Intratumoral heterogeneity (ITH) in hepatocellular carcinoma (HCC), driven by malignant cells plasticity, underlies differential responses to immune checkpoint inhibitors (ICIs). Single-nucleus sequencing revealed that hypoxic stress regulated malignant cellular plasticity, promoting transitions from an innate immune–responsive state to a non-responsive state with elevated lipid metabolism and angiogenesis. Whole-transcriptome sequencing revealed CircARSB was upregulated in responders and indicated better prognosis under ICIs treatment. Mechanistically, under normoxia, CircARSB activated the type I interferon–mediated innate immune pathway, whereas under hypoxia, it underwent m6A methylation and interacted with MOV10 to inhibit lipid metabolism. Exosomal CircARSB suppressed angiogenesis and facilitated ICI-responsive Kupffer cell subclusters. In vivo, under tyrosine kinase inhibitor (TKI)-alleviated hypoxia, adeno-associated virus (AAV)-delivered CircARSB remodeled the ICI-responsive tumor microenvironment by promoting CD8+ T cell infiltration, M1 macrophage polarization, and IFN-β production. Clinically, an MRI-based radiomics model (Circ-DWI with HIF1A-ADC) was developed to guide personalized treatment ICIs, alone or in combination with TKIs or CircARSB. Collectively, hypoxia-related CircARSB emerges as a promising biomarker for therapeutic response stratification and a potential target to enhance the efficacy of ICIs-based therapy in HCC.
{"title":"Hypoxia-related CircARSB Modulates lipid metabolism and innate immune crosstalk to influence immune checkpoint inhibitor response in hepatocellular carcinoma","authors":"Lina Song , Jialiang Cai , Guiqi Zhu , Peiling Zhang , Shiping Chen , Bing Quan , Junxian Du , Yufan Cai , Lele Song , Jian Zhou , Jia Fan , Tao Li , Lei Yu , Zhi Dai","doi":"10.1016/j.canlet.2025.218188","DOIUrl":"10.1016/j.canlet.2025.218188","url":null,"abstract":"<div><div>Intratumoral heterogeneity (ITH) in hepatocellular carcinoma (HCC), driven by malignant cells plasticity, underlies differential responses to immune checkpoint inhibitors (ICIs). Single-nucleus sequencing revealed that hypoxic stress regulated malignant cellular plasticity, promoting transitions from an innate immune–responsive state to a non-responsive state with elevated lipid metabolism and angiogenesis. Whole-transcriptome sequencing revealed CircARSB was upregulated in responders and indicated better prognosis under ICIs treatment. Mechanistically, under normoxia, CircARSB activated the type I interferon–mediated innate immune pathway, whereas under hypoxia, it underwent m<sup>6</sup>A methylation and interacted with MOV10 to inhibit lipid metabolism. Exosomal CircARSB suppressed angiogenesis and facilitated ICI-responsive Kupffer cell subclusters. In vivo, under tyrosine kinase inhibitor (TKI)-alleviated hypoxia, adeno-associated virus (AAV)-delivered CircARSB remodeled the ICI-responsive tumor microenvironment by promoting CD8<sup>+</sup> T cell infiltration, M1 macrophage polarization, and IFN-β production. Clinically, an MRI-based radiomics model (Circ-DWI with HIF1A-ADC) was developed to guide personalized treatment ICIs, alone or in combination with TKIs or CircARSB. Collectively, hypoxia-related CircARSB emerges as a promising biomarker for therapeutic response stratification and a potential target to enhance the efficacy of ICIs-based therapy in HCC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218188"},"PeriodicalIF":10.1,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145699511","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 : 2025-12-04DOI: 10.1016/j.canlet.2025.218205
Lujun Chen , Heming Li , Qiuhua Luo , Haitao Zhou , Haoran Song , Xiaofang Liu , Mingfang Zhao , Tao Han , Kai Li
Portal vein tumor thrombus (PVTT) is a major contributor to recurrence, metastasis, and poor prognosis in hepatocellular carcinoma (HCC). Effective early detection and therapeutic strategies for PVTT are lacking. In our ongoing investigation, we identified cell surface vimentin-positive (CSV+) CTCs as a key subpopulation enriched in HCC patients with PVTT, whereas conventional EpCAM+ CTCs exhibited limited clinical relevance. Integrated multi-omics analyses further revealed that tumor cells within the primary lesion exhibiting both epithelial-mesenchymal transition (EMT) and ferroptosis-associated signatures are more likely to intravasate and contribute to PVTT formation. Notably, G6PD was identified as a ferroptosis-related marker specifically enriched in this EMT-like tumor cell subset, suggesting its functional involvement in PVTT pathogenesis. Clinically, elevated levels of G6PD+CSV+ CTCs were associated with poor responses to targeted immunotherapy. Importantly, the identification of CSV also provides a rationale for developing CSV-guided delivery systems, enabling targeted silencing of PVTT-associated molecular drivers such as G6PD. Collectively, our findings highlight G6PD+CSV+ CTCs as a dual-function biomarker for both PVTT risk stratification and treatment response monitoring, offering a novel strategy for the precision management of advanced HCC with PVTT involvement.
{"title":"G6PD+CSV+ circulating tumor cells associated with portal vein tumor thrombus formation via EMT-ferroptosis crosstalk: a dual biomarker for therapeutic efficacy and prognosis prediction in hepatocellular carcinoma","authors":"Lujun Chen , Heming Li , Qiuhua Luo , Haitao Zhou , Haoran Song , Xiaofang Liu , Mingfang Zhao , Tao Han , Kai Li","doi":"10.1016/j.canlet.2025.218205","DOIUrl":"10.1016/j.canlet.2025.218205","url":null,"abstract":"<div><div>Portal vein tumor thrombus (PVTT) is a major contributor to recurrence, metastasis, and poor prognosis in hepatocellular carcinoma (HCC). Effective early detection and therapeutic strategies for PVTT are lacking. In our ongoing investigation, we identified cell surface vimentin-positive (CSV<sup>+</sup>) CTCs as a key subpopulation enriched in HCC patients with PVTT, whereas conventional EpCAM<sup>+</sup> CTCs exhibited limited clinical relevance. Integrated multi-omics analyses further revealed that tumor cells within the primary lesion exhibiting both epithelial-mesenchymal transition (EMT) and ferroptosis-associated signatures are more likely to intravasate and contribute to PVTT formation. Notably, G6PD was identified as a ferroptosis-related marker specifically enriched in this EMT-like tumor cell subset, suggesting its functional involvement in PVTT pathogenesis. Clinically, elevated levels of G6PD<sup>+</sup>CSV<sup>+</sup> CTCs were associated with poor responses to targeted immunotherapy. Importantly, the identification of CSV also provides a rationale for developing CSV-guided delivery systems, enabling targeted silencing of PVTT-associated molecular drivers such as G6PD. Collectively, our findings highlight G6PD<sup>+</sup>CSV<sup>+</sup> CTCs as a dual-function biomarker for both PVTT risk stratification and treatment response monitoring, offering a novel strategy for the precision management of advanced HCC with PVTT involvement.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218205"},"PeriodicalIF":10.1,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696050","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: 10.1016/j.canlet.2025.218203
Xue Dong , Ruyue Li , Xiujing Yao , Ying Li , Wenjie Chen , Hao An , Jiaxuan Chen , Chuankun Han , Yintao Li
Immune checkpoint inhibitors have revolutionized the treatment of advanced non-small cell lung cancer, yet the optimal duration of therapy remains uncertain, raising concerns about cumulative toxicity, economic burden, and potential overtreatment. We analyzed the current evidence comparing fixed-duration regimens (typically capped at 2 years) with continuous treatment until disease progression or unacceptable toxicity, focusing on their impact on long-term survival, disease control, and adverse event risks. Biomarkers, particularly circulating tumor DNA kinetics, play a critical role in guiding individualized treatment duration, providing greater precision in monitoring disease response and tailoring therapy. Additionally, we discuss different approaches for managing patients after treatment discontinuation, such as rechallenging following immune-related adverse events (irAEs).This review summarizes the current evidence on fixed versus indefinite immunotherapy duration and proposes a biomarker-informed, patient-centered framework for optimizing immunotherapy duration, aiming to balance therapeutic efficacy and minimize toxicity.
{"title":"Strategies to optimize duration of immunotherapy in advanced NSCLC: Current evidence and future directions","authors":"Xue Dong , Ruyue Li , Xiujing Yao , Ying Li , Wenjie Chen , Hao An , Jiaxuan Chen , Chuankun Han , Yintao Li","doi":"10.1016/j.canlet.2025.218203","DOIUrl":"10.1016/j.canlet.2025.218203","url":null,"abstract":"<div><div>Immune checkpoint inhibitors have revolutionized the treatment of advanced non-small cell lung cancer, yet the optimal duration of therapy remains uncertain, raising concerns about cumulative toxicity, economic burden, and potential overtreatment. We analyzed the current evidence comparing fixed-duration regimens (typically capped at 2 years) with continuous treatment until disease progression or unacceptable toxicity, focusing on their impact on long-term survival, disease control, and adverse event risks. Biomarkers, particularly circulating tumor DNA kinetics, play a critical role in guiding individualized treatment duration, providing greater precision in monitoring disease response and tailoring therapy. Additionally, we discuss different approaches for managing patients after treatment discontinuation, such as rechallenging following immune-related adverse events (irAEs).This review summarizes the current evidence on fixed versus indefinite immunotherapy duration and proposes a biomarker-informed, patient-centered framework for optimizing immunotherapy duration, aiming to balance therapeutic efficacy and minimize toxicity.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218203"},"PeriodicalIF":10.1,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687048","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 : 2025-12-02DOI: 10.1016/j.canlet.2025.218194
Hui Tian , Dan Zhao , Zhuan Zhou , Alex Kim , Huocong Huang , Yong J. Lee , Zhaoxia Qu , Rui Kang , Herbert J. Zeh , Kenneth D. Westover , Xinxin Song
Kirsten rat sarcoma (KRAS) mutations are among the most common oncogenic drivers in human cancers, particularly in non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). The development of allele-specific KRAS inhibitors, especially those targeting the KRASG12C variant, represents a landmark achievement in precision oncology. Yet their therapeutic benefit is often transient, as tumors rapidly develop seemingly heterogeneous resistance mechanisms. Increasing evidence implicates SRC, a non-receptor tyrosine kinase frequently hyperactivated in KRAS-mutant cancers, as a central regulator of resistance. This review integrates current evidence supporting SRC's role in mediating diverse resistance pathways, including mitogen-activated protein kinase (MAPK) reactivation, transcriptional/epigenetic reprogramming, metabolic adaptation, multidrug resistance, cell death evasion, and remodeling of the tumor microenvironment. We also critically examine the shortcomings of early-generation SRC inhibitors in solid tumors and highlight emerging therapeutic avenues such as next-generation inhibitors, proteolysis-targeting chimera (PROTAC) degraders, and biomarker-guided combination strategies. By connecting molecular insights with preclinical and clinical findings, this review positions SRC as a therapeutically actionable vulnerability in KRAS-driven cancers and outlines a translational framework for overcoming drug resistance.
{"title":"SRC at the crossroads of KRAS inhibitor resistance: Mechanisms and therapeutic opportunities","authors":"Hui Tian , Dan Zhao , Zhuan Zhou , Alex Kim , Huocong Huang , Yong J. Lee , Zhaoxia Qu , Rui Kang , Herbert J. Zeh , Kenneth D. Westover , Xinxin Song","doi":"10.1016/j.canlet.2025.218194","DOIUrl":"10.1016/j.canlet.2025.218194","url":null,"abstract":"<div><div>Kirsten rat sarcoma (KRAS) mutations are among the most common oncogenic drivers in human cancers, particularly in non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). The development of allele-specific KRAS inhibitors, especially those targeting the KRAS<sup>G12C</sup> variant, represents a landmark achievement in precision oncology. Yet their therapeutic benefit is often transient, as tumors rapidly develop seemingly heterogeneous resistance mechanisms. Increasing evidence implicates SRC, a non-receptor tyrosine kinase frequently hyperactivated in KRAS-mutant cancers, as a central regulator of resistance. This review integrates current evidence supporting SRC's role in mediating diverse resistance pathways, including mitogen-activated protein kinase (MAPK) reactivation, transcriptional/epigenetic reprogramming, metabolic adaptation, multidrug resistance, cell death evasion, and remodeling of the tumor microenvironment. We also critically examine the shortcomings of early-generation SRC inhibitors in solid tumors and highlight emerging therapeutic avenues such as next-generation inhibitors, proteolysis-targeting chimera (PROTAC) degraders, and biomarker-guided combination strategies. By connecting molecular insights with preclinical and clinical findings, this review positions SRC as a therapeutically actionable vulnerability in KRAS-driven cancers and outlines a translational framework for overcoming drug resistance.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218194"},"PeriodicalIF":10.1,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145658694","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: 10.1016/j.canlet.2025.218185
Tao Jiang , Do-Hyun Nam , Zvi Ram , Wai-sang Poo , Jiguang Wang , Damdindorj Boldbaatar , Ying Mao , Wenbin Ma , Qing Mao , Yongping You , Chuanlu Jiang , Xuejun Yang , Vinay Tergaonkar , Wei Zhang , Zheng Wang , Chunsheng Kang , Xiaoguang Qiu , Shaowu Li , Ling Chen , Xuejun Li , Yu Wang
It has been five years since the last version of the clinical practice guidelines for the management of adult diffuse gliomas was published by the Asian Glioma Genome Atlas (AGGA). Significant progress and revisions have occurred in the diagnosis and treatment of adult diffuse gliomas in recent years. In response to these updates, the joint guideline committee of the Chinese Glioma Cooperative Group (CGCG), the Society for Neuro-Oncology of China (SNO-China), and the Chinese Brain Cancer Association (CBCA) has revised the clinical practice guidelines. This updated guideline emphasizes molecular and pathological diagnostics, as well as the primary treatment modalities of surgery, radiotherapy, chemotherapy, and targeted therapy. Additionally, we have incorporated findings from recent clinical trials of new therapies to align with cutting-edge treatment strategies. This guideline is designed to serve as a practical resource for all professionals involved in managing adult diffuse glioma patients, while also providing valuable information for insurance companies and other institutions responsible for regulating cancer care costs in China and beyond.
{"title":"Updated clinical practice guidelines for the management of adult diffuse gliomas","authors":"Tao Jiang , Do-Hyun Nam , Zvi Ram , Wai-sang Poo , Jiguang Wang , Damdindorj Boldbaatar , Ying Mao , Wenbin Ma , Qing Mao , Yongping You , Chuanlu Jiang , Xuejun Yang , Vinay Tergaonkar , Wei Zhang , Zheng Wang , Chunsheng Kang , Xiaoguang Qiu , Shaowu Li , Ling Chen , Xuejun Li , Yu Wang","doi":"10.1016/j.canlet.2025.218185","DOIUrl":"10.1016/j.canlet.2025.218185","url":null,"abstract":"<div><div>It has been five years since the last version of the clinical practice guidelines for the management of adult diffuse gliomas was published by the Asian Glioma Genome Atlas (AGGA). Significant progress and revisions have occurred in the diagnosis and treatment of adult diffuse gliomas in recent years. In response to these updates, the joint guideline committee of the Chinese Glioma Cooperative Group (CGCG), the Society for Neuro-Oncology of China (SNO-China), and the Chinese Brain Cancer Association (CBCA) has revised the clinical practice guidelines. This updated guideline emphasizes molecular and pathological diagnostics, as well as the primary treatment modalities of surgery, radiotherapy, chemotherapy, and targeted therapy. Additionally, we have incorporated findings from recent clinical trials of new therapies to align with cutting-edge treatment strategies. This guideline is designed to serve as a practical resource for all professionals involved in managing adult diffuse glioma patients, while also providing valuable information for insurance companies and other institutions responsible for regulating cancer care costs in China and beyond.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"640 ","pages":"Article 218185"},"PeriodicalIF":10.1,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145667132","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号