The most widely accepted hypothesis for glioblastoma development posits that glioblastoma stem-like cells (GSCs) play a central role in tumor initiation, recurrence, and resistance to both chemotherapy and radiotherapy. We and others previously showed the importance of Mesenchyme Homeobox 2 (MEOX2) in supporting GSC survival and metabolism. In the present work, we demonstrate that MEOX2 also promotes DNA damage repair and contributes to resistance against genotoxic therapies in GSCs. Using a GLICO (GLioblastoma Cerebral Organoid) model, we show that MEOX2 knockdown impairs tumor growth and increases sensitivity to temozolomide (TMZ). Mechanistically, we find that MEOX2 depletion in 2D culture systems compromises genomic stability and impairs DNA repair. Co-immunoprecipitation and mass spectrometry analyses identified poly ADP-ribose polymerase 1 (PARP1) as a novel MEOX2 interactor. Consistent with this, MEOX2-depleted cells exhibit reduced PARylation levels and increased sensitivity to the PARP1 inhibitor Talazoparib, highlighting a potential therapeutic vulnerability.
Altogether, our findings reveal a previously unrecognized role for MEOX2 in the DNA damage response of GSCs, particularly in promoting survival and recovery after chemotherapy and ionizing radiation. These results also suggest that MEOX2 functions as a partner of PARP1 and may represent a promising therapeutic target in GBM.
{"title":"MEOX2 enhances DNA repair and therapy resistance in Glioblastoma stem-like cells via PARP1 interaction","authors":"Monia Russo , Elvia Valentini , Vincenza Aliperti , Federico Copparoni , Amanda Linkous , Claudia Montaldo , Silvia Soddu , Jean-Maxime Besson , Marie Lopez , Manuela Helmer Citterich , Alessandro Michienzi , Marco Tripodi , Silvia Anna Ciafrè , Silvia Galardi","doi":"10.1016/j.canlet.2026.218284","DOIUrl":"10.1016/j.canlet.2026.218284","url":null,"abstract":"<div><div>The most widely accepted hypothesis for glioblastoma development posits that glioblastoma stem-like cells (GSCs) play a central role in tumor initiation, recurrence, and resistance to both chemotherapy and radiotherapy. We and others previously showed the importance of Mesenchyme Homeobox 2 (MEOX2) in supporting GSC survival and metabolism. In the present work, we demonstrate that MEOX2 also promotes DNA damage repair and contributes to resistance against genotoxic therapies in GSCs. Using a GLICO (GLioblastoma Cerebral Organoid) model, we show that MEOX2 knockdown impairs tumor growth and increases sensitivity to temozolomide (TMZ). Mechanistically, we find that MEOX2 depletion in 2D culture systems compromises genomic stability and impairs DNA repair. Co-immunoprecipitation and mass spectrometry analyses identified poly ADP-ribose polymerase 1 (PARP1) as a novel MEOX2 interactor. Consistent with this, MEOX2-depleted cells exhibit reduced PARylation levels and increased sensitivity to the PARP1 inhibitor Talazoparib, highlighting a potential therapeutic vulnerability.</div><div>Altogether, our findings reveal a previously unrecognized role for MEOX2 in the DNA damage response of GSCs, particularly in promoting survival and recovery after chemotherapy and ionizing radiation. These results also suggest that MEOX2 functions as a partner of PARP1 and may represent a promising therapeutic target in GBM.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"642 ","pages":"Article 218284"},"PeriodicalIF":10.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146090229","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}
Drug resistance remains a significant obstacle in cancer therapy, severely compromising therapeutic efficacy and patient survival outcomes. Targeted therapy is now a central strategy for cancers with defined molecular abnormalities, employing agents that interact with specific genetic or molecular targets. Immunotherapy has emerged as a transformative approach in oncology by enhancing the immune system's ability to identify and eradicate cancer cells. Although microbial communities are increasingly acknowledged for their involvement in tumorigenesis and metastasis, their impact on drug resistance, including resistance to chemotherapy, immunotherapy, and targeted therapy, remains insufficiently investigated. Clinical evidence further reveals significant correlations between microbiota composition and survival outcomes, such as progression-free survival and recurrence rates. Microbiota contribute to resistance through complex mechanisms. Pathogenic bacteria can impair chemotherapy by degrading drugs and suppressing immune responses, whereas certain beneficial bacteria may enhance immunity and modulate metabolism. Notably, intratumoral microbiota directly modulate chemoresistance development through localized actions within the tumor microenvironment. This review synthesizes clinical data and mechanistic studies to delineate microbial-drug interactions, emphasizing how pathogens drive resistance through multifactorial pathways while probiotics mitigate treatment toxicity and restore drug sensitivity. We further propose novel therapeutic strategies leveraging microbe-drug interplay to overcome resistance and alleviate chemotherapy side effects, offering new approaches to enhance the efficacy of immunotherapy and targeted therapy. These findings advance the understanding of microbial contributions to drug resistance and provide new directions for clinical application in precision cancer therapy.
{"title":"The role of the microbiota in cancer drug resistance and emerging therapeutic strategies","authors":"Chang Che , Yelu Zhou , Liyu Chen , Sifan Li, Daiming Fan, Yuanyuan Lu, Xiaodi Zhao","doi":"10.1016/j.canlet.2026.218305","DOIUrl":"10.1016/j.canlet.2026.218305","url":null,"abstract":"<div><div>Drug resistance remains a significant obstacle in cancer therapy, severely compromising therapeutic efficacy and patient survival outcomes. Targeted therapy is now a central strategy for cancers with defined molecular abnormalities, employing agents that interact with specific genetic or molecular targets. Immunotherapy has emerged as a transformative approach in oncology by enhancing the immune system's ability to identify and eradicate cancer cells. Although microbial communities are increasingly acknowledged for their involvement in tumorigenesis and metastasis, their impact on drug resistance, including resistance to chemotherapy, immunotherapy, and targeted therapy, remains insufficiently investigated. Clinical evidence further reveals significant correlations between microbiota composition and survival outcomes, such as progression-free survival and recurrence rates. Microbiota contribute to resistance through complex mechanisms. Pathogenic bacteria can impair chemotherapy by degrading drugs and suppressing immune responses, whereas certain beneficial bacteria may enhance immunity and modulate metabolism. Notably, intratumoral microbiota directly modulate chemoresistance development through localized actions within the tumor microenvironment. This review synthesizes clinical data and mechanistic studies to delineate microbial-drug interactions, emphasizing how pathogens drive resistance through multifactorial pathways while probiotics mitigate treatment toxicity and restore drug sensitivity. We further propose novel therapeutic strategies leveraging microbe-drug interplay to overcome resistance and alleviate chemotherapy side effects, offering new approaches to enhance the efficacy of immunotherapy and targeted therapy. These findings advance the understanding of microbial contributions to drug resistance and provide new directions for clinical application in precision cancer therapy.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"642 ","pages":"Article 218305"},"PeriodicalIF":10.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146149248","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 : 2026-04-01Epub Date: 2026-02-04DOI: 10.1016/j.canlet.2026.218299
Yu Bai , Zixi Liu , Xiao Zhai , Di Zhang , Shiqiang Liu , Qilong Xia , Lin Chen , Yongkang Shi , Yangwei Liao , Yuhui Liu , Zhenxiong Zhang , Simiao Xu , Jun Gong , Chunle Zhao , Min Wang , Xiuhui Shi , Feng Zhu , Renyi Qin
Cancer cells undergo metabolic reprogramming to meet the demands of rapid proliferation, survival and chemotherapy resistance. Targeting cancer-specific metabolic vulnerabilities offers a compelling strategy for therapeutic intervention. Owing to the Warburg effect and the unique tumor microenvironment, pancreatic ductal adenocarcinoma (PDAC) cells exhibit a high demand for glucose to sustain their energy metabolism. Here, we identify a novel regulatory mechanism controlling the cell surface abundance of glucose transporter 1 (GLUT1), mediated by RAB8A-dependent vesicular trafficking. RAB8A, a member of the RAS oncogene family, enhances GLUT1 membrane localization and thereby increases glucose uptake in PDAC cells. Mechanistically, we demonstrate that ubiquitin-specific peptidase 20 (USP20) negatively regulates RAB8A activation by selectively removing K48-linked polyubiquitin chains from its inactive form. Functional assays in vitro and in vivo validate the tumor-suppressive role of the USP20–RAB8A signaling axis. Furthermore, using primary PDAC cells derived from KPC (KrasG12D/+; Trp53 R172Hflox/flox; Pdx1-Cre) mice, we show that dual knockdown of Rab8a and Glut1 markedly attenuates tumor-promoting effects driven by oncogenic Kras and Trp53 loss. Collectively, our findings reveal that the USP20–RAB8A–GLUT1 axis regulates glucose uptake and metabolic reprogramming in PDAC, thereby inhibiting tumor growth and metastasis. Targeting this signaling axis provides a novel insight into metabolic therapy for pancreatic cancer.
{"title":"USP20–RAB8A signaling axis restricts pancreatic cancer progression by disrupting GLUT1 vesicular trafficking and inhibiting glucose uptake","authors":"Yu Bai , Zixi Liu , Xiao Zhai , Di Zhang , Shiqiang Liu , Qilong Xia , Lin Chen , Yongkang Shi , Yangwei Liao , Yuhui Liu , Zhenxiong Zhang , Simiao Xu , Jun Gong , Chunle Zhao , Min Wang , Xiuhui Shi , Feng Zhu , Renyi Qin","doi":"10.1016/j.canlet.2026.218299","DOIUrl":"10.1016/j.canlet.2026.218299","url":null,"abstract":"<div><div>Cancer cells undergo metabolic reprogramming to meet the demands of rapid proliferation, survival and chemotherapy resistance. Targeting cancer-specific metabolic vulnerabilities offers a compelling strategy for therapeutic intervention. Owing to the Warburg effect and the unique tumor microenvironment, pancreatic ductal adenocarcinoma (PDAC) cells exhibit a high demand for glucose to sustain their energy metabolism. Here, we identify a novel regulatory mechanism controlling the cell surface abundance of glucose transporter 1 (GLUT1), mediated by RAB8A-dependent vesicular trafficking. RAB8A, a member of the RAS oncogene family, enhances GLUT1 membrane localization and thereby increases glucose uptake in PDAC cells. Mechanistically, we demonstrate that ubiquitin-specific peptidase 20 (USP20) negatively regulates RAB8A activation by selectively removing K48-linked polyubiquitin chains from its inactive form. Functional assays in vitro and in vivo validate the tumor-suppressive role of the USP20–RAB8A signaling axis. Furthermore, using primary PDAC cells derived from KPC (<em>Kras</em><sup><em>G12D/+</em></sup><em>; Trp53 R172H</em><sup><em>flox/flox</em></sup><em>; Pdx1-Cre</em>) mice, we show that dual knockdown of Rab8a and Glut1 markedly attenuates tumor-promoting effects driven by oncogenic <em>Kras</em> and <em>Trp53</em> loss. Collectively, our findings reveal that the USP20–RAB8A–GLUT1 axis regulates glucose uptake and metabolic reprogramming in PDAC, thereby inhibiting tumor growth and metastasis. Targeting this signaling axis provides a novel insight into metabolic therapy for pancreatic cancer.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"642 ","pages":"Article 218299"},"PeriodicalIF":10.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131078","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 : 2026-04-01Epub Date: 2026-01-30DOI: 10.1016/j.canlet.2026.218282
Kai Yu , Jiazhu Sun , Jiawei Zhang , Yuchen Shi , Junyan Wang , Yuqing Wu , Dingheng Lu , Xinyang Niu , Yuxiao Li , Suyuelin Huang , Jihuan Yuan , Zhixiang Qi , Fenghao Zhang , Jiangfeng Li , Hong Chen , Ben Liu
Acquired resistance to cisplatin remains a major therapeutic challenge in muscle-invasive bladder cancer. Here, we demonstrate for the first time that lactate accumulation induces AARS2-dependent lactylation of the m6A reader YTHDF3, establishing lactylation as a previously unrecognized regulatory layer of this epitranscriptomic factor. YTHDF3 lactylation stabilizes the protein by antagonizing ubiquitin-mediated degradation. Importantly, a lactylation-deficient YTHDF3 mutant fails to confer cisplatin resistance, underscoring the functional importance of this modification. Mechanistically, lactylated YTHDF3 enhances its m6A-dependent recognition and decay of KDM6B RNA. The resulting downregulation of KDM6B suppresses CDKN1A transcription through impaired H3K27me3 demethylation, representing an epigenetic mechanism that weakens the DNA damage response and promotes chemoresistance. Functional assays further demonstrate that YTHDF3 knockdown enhances cisplatin sensitivity in bladder cancer cells and xenograft tumors, whereas enforced expression of KDM6B or CDKN1A phenocopies the cisplatin-sensitizing effect of YTHDF3 knockdown. Collectively, our findings define a lactate–AARS2–YTHDF3–KDM6B–CDKN1A axis that integrates metabolic reprogramming, m6A-dependent epitranscriptomic regulation, and epigenetic chromatin remodeling to drive cisplatin resistance in bladder cancer.
{"title":"Lactylation enhances YTHDF3 stability to promote cisplatin resistance via m6A-dependent KDM6B decay in bladder cancer","authors":"Kai Yu , Jiazhu Sun , Jiawei Zhang , Yuchen Shi , Junyan Wang , Yuqing Wu , Dingheng Lu , Xinyang Niu , Yuxiao Li , Suyuelin Huang , Jihuan Yuan , Zhixiang Qi , Fenghao Zhang , Jiangfeng Li , Hong Chen , Ben Liu","doi":"10.1016/j.canlet.2026.218282","DOIUrl":"10.1016/j.canlet.2026.218282","url":null,"abstract":"<div><div>Acquired resistance to cisplatin remains a major therapeutic challenge in muscle-invasive bladder cancer. Here, we demonstrate for the first time that lactate accumulation induces AARS2-dependent lactylation of the m6A reader YTHDF3, establishing lactylation as a previously unrecognized regulatory layer of this epitranscriptomic factor. YTHDF3 lactylation stabilizes the protein by antagonizing ubiquitin-mediated degradation. Importantly, a lactylation-deficient YTHDF3 mutant fails to confer cisplatin resistance, underscoring the functional importance of this modification. Mechanistically, lactylated YTHDF3 enhances its m6A-dependent recognition and decay of KDM6B RNA. The resulting downregulation of KDM6B suppresses CDKN1A transcription through impaired H3K27me3 demethylation, representing an epigenetic mechanism that weakens the DNA damage response and promotes chemoresistance. Functional assays further demonstrate that YTHDF3 knockdown enhances cisplatin sensitivity in bladder cancer cells and xenograft tumors, whereas enforced expression of KDM6B or CDKN1A phenocopies the cisplatin-sensitizing effect of YTHDF3 knockdown. Collectively, our findings define a lactate–AARS2–YTHDF3–KDM6B–CDKN1A axis that integrates metabolic reprogramming, m6A-dependent epitranscriptomic regulation, and epigenetic chromatin remodeling to drive cisplatin resistance in bladder cancer.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"642 ","pages":"Article 218282"},"PeriodicalIF":10.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146099886","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 : 2026-04-01Epub Date: 2026-02-06DOI: 10.1016/j.canlet.2026.218303
Xuezhen Wang , Minghuan Yang , Jinxin Li , Yufan Wu , Qiuyuan Yue , Xinkai Wang , Hailin Lan , Xiaoxia Li , Junjun Li , Yang Wang , Qichun Wei , Jinsheng Hong , Mingwei Zhang
Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. This study aimed to develop and validate a regulatory T cell (Treg)-associated magnetic resonance imaging (MRI) radiomics model and assess its prognostic value, cross-species similarity, and interpretability across multicenter cohorts. Tregs retained prognostic significance for patients with GBM under World Health Organization CNS 5 classification. In murine models, Treg depletion suppressed tumor growth and reduced the infiltration of myeloid-derived suppressor cells, tumor-associated macrophages, and exhausted CD8+T cells. The in vitro co-culture of Tregs with GL261 cells significantly reduced radiation-induced apoptosis. We constructed a Treg-associated radiomics model comprising six features and validated the prognostic value of the radiomics score (RS) across multicenter clinical imaging cohorts (First Affiliated Hospital of Fujian Medical University, n = 111, hazard ratio [HR] = 2.178, 95% confidence interval [CI]: 1.269–3.740; Second Affiliated Hospital of Zhejiang University School of Medicine, n = 126, HR = 1.664, 95% CI: 1.049–2.640; The Cancer Genome Atlas, n = 86, HR = 1.811, 95% CI: 1.089–3.010). Treg depletion experiments also confirmed causal associations between two radiomic features and Treg infiltration. RS stratification correlated with hypoxia, glycolysis, interleukin (IL)–2/signal transducer and activator of transcription (STAT) 5, and IL-6/Janus kinase/STAT3 signaling pathways and immune checkpoints and genomic alterations. The MRI radiomics model enables noninvasive prediction of Treg infiltration and serves as a robust, generalizable prognostic biomarker for GBM. These findings provide evidence for biological causal associations and cross-species similarities between radiomics features and Treg infiltration.
{"title":"Treg-driven magnetic resonance radiomics in glioblastoma: a multicenter and cross-species model for prognostic biomarker discovery","authors":"Xuezhen Wang , Minghuan Yang , Jinxin Li , Yufan Wu , Qiuyuan Yue , Xinkai Wang , Hailin Lan , Xiaoxia Li , Junjun Li , Yang Wang , Qichun Wei , Jinsheng Hong , Mingwei Zhang","doi":"10.1016/j.canlet.2026.218303","DOIUrl":"10.1016/j.canlet.2026.218303","url":null,"abstract":"<div><div>Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. This study aimed to develop and validate a regulatory T cell (Treg)-associated magnetic resonance imaging (MRI) radiomics model and assess its prognostic value, cross-species similarity, and interpretability across multicenter cohorts. Tregs retained prognostic significance for patients with GBM under World Health Organization CNS 5 classification. In murine models, Treg depletion suppressed tumor growth and reduced the infiltration of myeloid-derived suppressor cells, tumor-associated macrophages, and exhausted CD8<sup>+</sup>T cells. The <em>in vitro</em> co-culture of Tregs with GL261 cells significantly reduced radiation-induced apoptosis. We constructed a Treg-associated radiomics model comprising six features and validated the prognostic value of the radiomics score (RS) across multicenter clinical imaging cohorts (First Affiliated Hospital of Fujian Medical University, <em>n</em> = 111, hazard ratio [HR] = 2.178, 95% confidence interval [CI]: 1.269–3.740; Second Affiliated Hospital of Zhejiang University School of Medicine, <em>n</em> = 126, HR = 1.664, 95% CI: 1.049–2.640; The Cancer Genome Atlas, <em>n</em> = 86, HR = 1.811, 95% CI: 1.089–3.010). Treg depletion experiments also confirmed causal associations between two radiomic features and Treg infiltration. RS stratification correlated with hypoxia, glycolysis, interleukin (IL)–2/signal transducer and activator of transcription (STAT) 5, and IL-6/Janus kinase/STAT3 signaling pathways and immune checkpoints and genomic alterations. The MRI radiomics model enables noninvasive prediction of Treg infiltration and serves as a robust, generalizable prognostic biomarker for GBM. These findings provide evidence for biological causal associations and cross-species similarities between radiomics features and Treg infiltration.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"642 ","pages":"Article 218303"},"PeriodicalIF":10.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141146","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 : 2026-04-01Epub Date: 2026-01-31DOI: 10.1016/j.canlet.2026.218272
Qi Liu , Huawei Zhang , Senyan Wang , Cheng Ye , Wenjuan Wei , Jing Fu , Hongyang Wang , Xiaofang Zhao
This study analyzes the global burden of primary liver cancer among young adults (15–49 years) from 1990 to 2021, revealing a 46.0% rise in incidence and 59.0% increase in prevalence, yet declining age-standardized mortality (Estimated Annual Percentage Change-EAPC = −1.27). Middle-SDI regions faced the highest burden, with East Asia accounting for 66,472 prevalent cases and stark national disparities (e.g., Mongolia ASR = 1846.83/100,000 vs. Morocco ASR = 16.73). Population growth drove 42.8–47.8% of case increases, while metabolic risks and alcohol use (surpassing smoking in 2021) emerged as dominant factors. Males showed a 3.5-fold higher smoking-related risk than females. Deaths rose notably among those ≥30 years, with a 20.6% increase in 30–34-year-olds, signaling earlier onset. A shift from hepatitis B to metabolic/behavioral risks underscores evolving etiology. Projections suggest 133,561 cases by 2050, urging prioritized early screening and equitable resource allocation beyond traditional viral hepatitis frameworks.
{"title":"Burden of primary liver cancer and underlying etiologies among young adults from 1990 to 2021 and modelled Projection to 2050","authors":"Qi Liu , Huawei Zhang , Senyan Wang , Cheng Ye , Wenjuan Wei , Jing Fu , Hongyang Wang , Xiaofang Zhao","doi":"10.1016/j.canlet.2026.218272","DOIUrl":"10.1016/j.canlet.2026.218272","url":null,"abstract":"<div><div>This study analyzes the global burden of primary liver cancer among young adults (15–49 years) from 1990 to 2021, revealing a 46.0% rise in incidence and 59.0% increase in prevalence, yet declining age-standardized mortality (Estimated Annual Percentage Change-EAPC = −1.27). Middle-SDI regions faced the highest burden, with East Asia accounting for 66,472 prevalent cases and stark national disparities (e.g., Mongolia ASR = 1846.83/100,000 vs. Morocco ASR = 16.73). Population growth drove 42.8–47.8% of case increases, while metabolic risks and alcohol use (surpassing smoking in 2021) emerged as dominant factors. Males showed a 3.5-fold higher smoking-related risk than females. Deaths rose notably among those ≥30 years, with a 20.6% increase in 30–34-year-olds, signaling earlier onset. A shift from hepatitis B to metabolic/behavioral risks underscores evolving etiology. Projections suggest 133,561 cases by 2050, urging prioritized early screening and equitable resource allocation beyond traditional viral hepatitis frameworks.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"642 ","pages":"Article 218272"},"PeriodicalIF":10.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146103869","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 : 2026-03-31Epub Date: 2026-01-22DOI: 10.1016/j.canlet.2026.218279
Yujuan Jiang , Zitong Zhao , Liying Ma , Xinxin Shao , Peng Wang , Yongmei Song , Yantao Tian
Gastric signet-ring cell carcinoma (GSRCC) exhibits a poor prognosis because of its aggressive behavior and chemoresistance, which is strongly associated with dysregulated cholesterol metabolism. This study investigated the role of circUBR5 in GSRCC progression. CircUBR5 was identified by transcriptome sequencing of gastric cancer tissues and validated. CircUBR5 was upregulated in GSRCC and correlated with advanced stage, metastasis, and poor survival. Functionally, circUBR5 promoted the proliferation, metastasis, and cisplatin resistance of GSRCC cells in vitro and in vivo. Mechanistically, cytoplasmic circUBR5 functions as a sponge for miR-1208, thereby relieving miR-1208-mediated suppression of CYP19A1, a key estrogen synthesis-related enzyme, and activating estrogen signaling. Concurrently, circUBR5 directly binds to the cholesterol esterification enzyme ACAT1 and recruits the deubiquitinase PSMD14 to stabilize it, promoting cholesterol metabolic reprogramming. CircUBR5 can also be packaged into exosomes, which mediates chemoresistance transfer to recipient gastric adenocarcinoma cells. Notably, combining circUBR5-targeting antisense oligonucleotides with cisplatin synergistically inhibited tumor growth and reversed chemoresistance in vivo. Thus, circUBR5 promotes GSRCC progression through dual pathways coordinating estrogen signaling and cholesterol metabolism, and its exosomal dissemination facilitates chemoresistance induction within the tumor microenvironment, highlighting its potential as a prognostic biomarker and therapeutic target.
{"title":"Exosomal circUBR5 drives metastasis and chemoresistance in gastric signet-ring cell carcinoma by reprogramming cholesterol metabolism through the hsa-miR-1208/CYP19A1 axis and ACAT1 upregulation","authors":"Yujuan Jiang , Zitong Zhao , Liying Ma , Xinxin Shao , Peng Wang , Yongmei Song , Yantao Tian","doi":"10.1016/j.canlet.2026.218279","DOIUrl":"10.1016/j.canlet.2026.218279","url":null,"abstract":"<div><div>Gastric signet-ring cell carcinoma (GSRCC) exhibits a poor prognosis because of its aggressive behavior and chemoresistance, which is strongly associated with dysregulated cholesterol metabolism. This study investigated the role of circUBR5 in GSRCC progression. CircUBR5 was identified by transcriptome sequencing of gastric cancer tissues and validated. CircUBR5 was upregulated in GSRCC and correlated with advanced stage, metastasis, and poor survival. Functionally, circUBR5 promoted the proliferation, metastasis, and cisplatin resistance of GSRCC cells <em>in vitro and in vivo.</em> Mechanistically, cytoplasmic circUBR5 functions as a sponge for miR-1208, thereby relieving miR-1208-mediated suppression of CYP19A1, a key estrogen synthesis-related enzyme, and activating estrogen signaling. Concurrently, circUBR5 directly binds to the cholesterol esterification enzyme ACAT1 and recruits the deubiquitinase PSMD14 to stabilize it, promoting cholesterol metabolic reprogramming. CircUBR5 can also be packaged into exosomes, which mediates chemoresistance transfer to recipient gastric adenocarcinoma cells. Notably, combining circUBR5-targeting antisense oligonucleotides with cisplatin synergistically inhibited tumor growth and reversed chemoresistance <em>in vivo.</em> Thus, circUBR5 promotes GSRCC progression through dual pathways coordinating estrogen signaling and cholesterol metabolism, and its exosomal dissemination facilitates chemoresistance induction within the tumor microenvironment, highlighting its potential as a prognostic biomarker and therapeutic target.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218279"},"PeriodicalIF":10.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043601","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 : 2026-03-31Epub Date: 2026-01-17DOI: 10.1016/j.canlet.2026.218259
Yaning Yang , Chengming Liu , Lu Yang , Sufei Zheng , Haiyan Xu , Shuyang Zhang , Linyan Tian , Nan Sun , Jie He , Yan Wang
Primary resistance to first-line chemoimmunotherapy remains a significant challenge in treating advanced non-small cell lung cancer (NSCLC). Although cytokines such as interleukin-6 (IL-6) have been implicated in resistance to immune checkpoint inhibitor (ICI) monotherapy, their predictive value for chemoimmunotherapy outcomes and the underlying mechanisms are less defined. This study investigated the prognostic significance of the baseline plasma IL-6 levels and the role of this cytokine in shaping the tumour immune microenvironment (TIME) of NSCLC. Here, we retrospectively analysed data on 123 advanced NSCLC patients treated with anti-PD-1 inhibitors plus chemotherapy. Baseline plasma IL-6 levels were measured via ELISA. Progression-free survival (PFS) and overall survival (OS) were assessed via Kaplan-Meier and Cox regression analyses. We established murine lung adenocarcinoma (LLC) and squamous cell carcinoma (KLN205) models with IL-6 overexpression or inhibition and treated them with anti-PD-1 therapy ± chemotherapy. Tumour growth was monitored, and single-cell RNA sequencing (scRNA-seq) was performed on tumour-infiltrating immune cells. The results showed that patients with high baseline plasma IL-6 levels (>7.002 pg/mL) exhibited significantly worse PFS (median: 7.20 vs. 16.63 months, P = 0.001) and OS (median: 15.63 vs. 32.80 months, P = 0.001) than those with low baseline levels. A high IL-6 level was an independent predictor of worse PFS (HR = 2.42, P < 0.001) and OS (HR = 2.96, P < 0.001) and was correlated with progressive disease (PD, P = 0.018). In murine models, IL-6 overexpression diminished the antitumour efficacy of anti-PD-1 therapy combined with chemotherapy. Moreover, scRNA-seq analysis revealed that IL-6 overexpression skewed macrophage polarisation toward immunosuppressive phenotypes (characterised by Hilpda and Nr4a1 expression) and reduced the proportion of cytotoxic CD8+ T-cells while increasing the proportion of regulatory T-cells (Tregs). Conversely, IL-6 inhibition promoted an immunostimulatory macrophage phenotype (characterised by increased Ccl8 expression) and enhanced CD8+ T-cell infiltration and function. A high IL-6 level was also correlated with impairment of NK cell degranulation pathways. These findings uncovered that an elevated baseline plasma IL-6 level is a robust independent predictor of primary resistance and poor survival in advanced NSCLC patients receiving chemoimmunotherapy. Mechanistically, IL-6 drives formation of an immunosuppressive TIME by promoting protumour macrophage polarisation. This, in turn, suppress cytotoxic T cell infiltration, promoting Treg expansion, and impairing NK cell function, indicating that the targeting of IL-6 represents a promising strategy to overcome resistance to chemoimmunotherapy.
一线化学免疫治疗的原发性耐药仍然是晚期非小细胞肺癌（NSCLC）治疗的一个重大挑战。尽管白细胞介素-6 （IL-6）等细胞因子与免疫检查点抑制剂（ICI）单一疗法的耐药性有关，但它们对化学免疫治疗结果的预测价值和潜在机制尚不明确。本研究探讨血浆IL-6基线水平对非小细胞肺癌预后的意义及其在肿瘤免疫微环境（TIME）形成中的作用。在这里，我们回顾性分析了123例接受抗pd -1抑制剂加化疗治疗的晚期非小细胞肺癌患者的数据。ELISA法测定血浆IL-6基线水平。通过Kaplan-Meier和Cox回归分析评估无进展生存期（PFS）和总生存期（OS）。我们建立IL-6过表达（IL6a）或抑制（IL6i）的小鼠肺腺癌（LLC）和鳞状细胞癌（KLN205）模型，并采用抗pd -1治疗±化疗。监测肿瘤生长情况，并对肿瘤浸润免疫细胞进行单细胞RNA测序（scRNA-seq）。结果显示，高基线血浆IL-6水平（>7.002 pg/mL）患者的PFS（中位数：7.20 vs. 16.63个月，P=0.001）和OS（中位数：15.63 vs. 32.80个月，P=0.001）明显低于低基线水平患者。高IL-6水平是PFS恶化的独立预测因子（HR=2.42， P+ t细胞，同时增加调节性t细胞（Tregs）的比例）。相反，IL-6抑制促进了免疫刺激的巨噬细胞表型（以Ccl8表达增加为特征），增强了CD8+ t细胞的浸润和功能。高IL-6水平也与NK细胞脱颗粒通路的损伤相关。这些研究结果表明，血浆IL-6基线水平升高是接受一线化疗免疫治疗的晚期NSCLC患者原发性耐药和生存不良的可靠独立预测因子。从机制上讲，IL-6通过促进原肿瘤巨噬细胞极化来驱动免疫抑制TIME的形成。这反过来又抑制细胞毒性T细胞浸润，促进Treg扩增，损害NK细胞功能，表明靶向IL-6代表了克服化学免疫治疗耐药的有希望的策略。
{"title":"IL-6 drives chemoimmunotherapy resistance in NSCLC by reprogramming myeloid cells and impairing cytotoxic lymphocyte function","authors":"Yaning Yang , Chengming Liu , Lu Yang , Sufei Zheng , Haiyan Xu , Shuyang Zhang , Linyan Tian , Nan Sun , Jie He , Yan Wang","doi":"10.1016/j.canlet.2026.218259","DOIUrl":"10.1016/j.canlet.2026.218259","url":null,"abstract":"<div><div>Primary resistance to first-line chemoimmunotherapy remains a significant challenge in treating advanced non-small cell lung cancer (NSCLC). Although cytokines such as interleukin-6 (IL-6) have been implicated in resistance to immune checkpoint inhibitor (ICI) monotherapy, their predictive value for chemoimmunotherapy outcomes and the underlying mechanisms are less defined. This study investigated the prognostic significance of the baseline plasma IL-6 levels and the role of this cytokine in shaping the tumour immune microenvironment (TIME) of NSCLC. Here, we retrospectively analysed data on 123 advanced NSCLC patients treated with anti-PD-1 inhibitors plus chemotherapy. Baseline plasma IL-6 levels were measured via ELISA. Progression-free survival (PFS) and overall survival (OS) were assessed via Kaplan-Meier and Cox regression analyses. We established murine lung adenocarcinoma (LLC) and squamous cell carcinoma (KLN205) models with IL-6 overexpression or inhibition and treated them with anti-PD-1 therapy ± chemotherapy. Tumour growth was monitored, and single-cell RNA sequencing (scRNA-seq) was performed on tumour-infiltrating immune cells. The results showed that patients with high baseline plasma IL-6 levels (>7.002 pg/mL) exhibited significantly worse PFS (median: 7.20 vs. 16.63 months, P = 0.001) and OS (median: 15.63 vs. 32.80 months, P = 0.001) than those with low baseline levels. A high IL-6 level was an independent predictor of worse PFS (HR = 2.42, P < 0.001) and OS (HR = 2.96, P < 0.001) and was correlated with progressive disease (PD, P = 0.018). In murine models, IL-6 overexpression diminished the antitumour efficacy of anti-PD-1 therapy combined with chemotherapy. Moreover, scRNA-seq analysis revealed that IL-6 overexpression skewed macrophage polarisation toward immunosuppressive phenotypes (characterised by Hilpda and Nr4a1 expression) and reduced the proportion of cytotoxic CD8<sup>+</sup> T-cells while increasing the proportion of regulatory T-cells (Tregs). Conversely, IL-6 inhibition promoted an immunostimulatory macrophage phenotype (characterised by increased Ccl8 expression) and enhanced CD8<sup>+</sup> T-cell infiltration and function. A high IL-6 level was also correlated with impairment of NK cell degranulation pathways. These findings uncovered that an elevated baseline plasma IL-6 level is a robust independent predictor of primary resistance and poor survival in advanced NSCLC patients receiving chemoimmunotherapy. Mechanistically, IL-6 drives formation of an immunosuppressive TIME by promoting protumour macrophage polarisation. This, in turn, suppress cytotoxic T cell infiltration, promoting Treg expansion, and impairing NK cell function, indicating that the targeting of IL-6 represents a promising strategy to overcome resistance to chemoimmunotherapy.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218259"},"PeriodicalIF":10.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003281","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 : 2026-03-31Epub Date: 2026-01-14DOI: 10.1016/j.canlet.2026.218256
Yueqin Diao , Xiao Chen , Ziyan Huang , Qian Tan , Meng Yang , Hanyi Yu , Yanwu Xu , Xing Hu
The rapid development of multimodal large language models (LLMs) such as GPT and Med-PaLM is reshaping medical practice. Skin cancer, one of the most prevalent malignancies, encompasses diverse subtypes and early signs that often resemble benign lesions, making timely detection and accurate diagnosis challenging. Traditional diagnostic methods are hindered by subjectivity, sampling bias, and low efficiency. Skin cancer diagnosis is largely constrained by strong subjectivity, sampling bias, and low diagnostic efficiency regularly. Although immunotherapy and targeted therapy aimed at the tumor microenvironment have brought new therapeutic possibilities to patients, tumor heterogeneity and immune evasion remain major unresolved challenges. Artificial intelligence techniques based on deep learning and complex neural networks can integrate dermoscopic images, histopathological information, and genetic databases through multimodal fusion strategies, enabling the extraction of richer and complementary features and thereby significantly improving diagnostic accuracy and robustness. Moreover, tailoring treatment strategies according to individual patient characteristics facilitates truly personalized therapy and prognostic assessment. In the field of drug development, artificial intelligence accelerates the screening and simulation of candidate compounds, substantially reducing development time and expenditure. This review summarizes recent advances in AI for skin cancer, with emphasis on early detection, individualized therapy, and patient management. We further discuss challenges related to data quality and model interpretability, emphasizing the importance of dermatology-specific foundation models and collaboration between clinicians and engineers.
{"title":"Cutting-edge AI technologies in skin cancer applications","authors":"Yueqin Diao , Xiao Chen , Ziyan Huang , Qian Tan , Meng Yang , Hanyi Yu , Yanwu Xu , Xing Hu","doi":"10.1016/j.canlet.2026.218256","DOIUrl":"10.1016/j.canlet.2026.218256","url":null,"abstract":"<div><div>The rapid development of multimodal large language models (LLMs) such as GPT and Med-PaLM is reshaping medical practice. Skin cancer, one of the most prevalent malignancies, encompasses diverse subtypes and early signs that often resemble benign lesions, making timely detection and accurate diagnosis challenging. Traditional diagnostic methods are hindered by subjectivity, sampling bias, and low efficiency. Skin cancer diagnosis is largely constrained by strong subjectivity, sampling bias, and low diagnostic efficiency regularly. Although immunotherapy and targeted therapy aimed at the tumor microenvironment have brought new therapeutic possibilities to patients, tumor heterogeneity and immune evasion remain major unresolved challenges. Artificial intelligence techniques based on deep learning and complex neural networks can integrate dermoscopic images, histopathological information, and genetic databases through multimodal fusion strategies, enabling the extraction of richer and complementary features and thereby significantly improving diagnostic accuracy and robustness. Moreover, tailoring treatment strategies according to individual patient characteristics facilitates truly personalized therapy and prognostic assessment. In the field of drug development, artificial intelligence accelerates the screening and simulation of candidate compounds, substantially reducing development time and expenditure. This review summarizes recent advances in AI for skin cancer, with emphasis on early detection, individualized therapy, and patient management. We further discuss challenges related to data quality and model interpretability, emphasizing the importance of dermatology-specific foundation models and collaboration between clinicians and engineers<strong>.</strong></div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218256"},"PeriodicalIF":10.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988121","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 : 2026-03-31Epub Date: 2026-01-21DOI: 10.1016/j.canlet.2026.218278
Fada Xia , Xudong Zhu , Xiaoyan Li , Qiaoli Yi , Shangjun Zhou , Jiayu Wang , Xia Wang , Kejing Zhang , Cheng Zhan , Hailin Tang , Zhijie Xu , Huiting Zhang , Anli Yang , Yuanliang Yan
Factor-induced gene 4 (FIG4) has been recently identified as a lipid-modifying enzyme that plays an important role in controls autophagolysosomal activity. However, the regulatory mechanisms and biological functions of FIG4 in cancer therapeutic resistance are not well defined. In this study, we identify that FIG4 as a regulator of IL-18 autophagy–lysosomal degradation, participating in the immunotherapy response in triple-negative breast cancer (TNBC). FIG4 overexpression markedly facilitate the autophagy–lysosomal degradation of IL-18 in the LAMP2A-dependent manner. Ubiquitinated IL-18 induced by FIG4 overexpression reduces its secretion, inhibiting the tumor infiltration of immune-suppressive lipid-associated macrophages (LAMs) and re-sensitizing TNBC to immune-checkpoint blockade. Notably, the combination of FIG4 overexpression or IL-18 neutralizing antibody (aIL-18) with PD-1 inhibitor (aPD-1) produces synergistic effects, effectively addressing certain limitations of current immunotherapeutic approaches in TNBC. In conclusion, these findings underscore a novel mechanism underlying the roles of FIG4-IL-18 axis in immunotherapy resistance. Targeting FIG4–IL-18 axis offers a tractable strategy to dismantle LAM-mediated immunotherapy resistance in TNBC.
{"title":"FIG4 downregulation-arrested autophagy-lysosomal degradation of IL-18 drives lipid-associated macrophage polarization and immunotherapy resistance in triple-negative breast cancer","authors":"Fada Xia , Xudong Zhu , Xiaoyan Li , Qiaoli Yi , Shangjun Zhou , Jiayu Wang , Xia Wang , Kejing Zhang , Cheng Zhan , Hailin Tang , Zhijie Xu , Huiting Zhang , Anli Yang , Yuanliang Yan","doi":"10.1016/j.canlet.2026.218278","DOIUrl":"10.1016/j.canlet.2026.218278","url":null,"abstract":"<div><div>Factor-induced gene 4 (FIG4) has been recently identified as a lipid-modifying enzyme that plays an important role in controls autophagolysosomal activity. However, the regulatory mechanisms and biological functions of FIG4 in cancer therapeutic resistance are not well defined. In this study, we identify that FIG4 as a regulator of IL-18 autophagy–lysosomal degradation, participating in the immunotherapy response in triple-negative breast cancer (TNBC). FIG4 overexpression markedly facilitate the autophagy–lysosomal degradation of IL-18 in the LAMP2A-dependent manner. Ubiquitinated IL-18 induced by FIG4 overexpression reduces its secretion, inhibiting the tumor infiltration of immune-suppressive lipid-associated macrophages (LAMs) and re-sensitizing TNBC to immune-checkpoint blockade. Notably, the combination of FIG4 overexpression or IL-18 neutralizing antibody (aIL-18) with PD-1 inhibitor (aPD-1) produces synergistic effects, effectively addressing certain limitations of current immunotherapeutic approaches in TNBC. In conclusion, these findings underscore a novel mechanism underlying the roles of FIG4-IL-18 axis in immunotherapy resistance. Targeting FIG4–IL-18 axis offers a tractable strategy to dismantle LAM-mediated immunotherapy resistance in TNBC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"641 ","pages":"Article 218278"},"PeriodicalIF":10.1,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040188","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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