Pub Date : 2025-12-11DOI: 10.1016/j.canlet.2025.218218
Baiyang Liu , Xudong Xiang , Yan Cheng , Jimin Fei , Mengge Wu , Laihao Qu , Xian Zhao , Xing Chen , Yao Li , Jia Du , Dengcai Mu , Haoqing Zhai , Qiushuo Shen , Yongbin Chen , Cuiping Yang
Head and neck squamous cell carcinoma (HNSCC) is an epithelial carcinoma characterized by its distinct geographical distribution, exhibiting a higher prevalence in Southeast Asia. Despite the approval of immune checkpoint blockade (ICB) therapy for treating advanced recurrent HNSCC, the extent of patient benefit remains limited. Elucidating the molecular regulatory mechanisms of immunosuppressive tumor microenvironment in HNSCC is crucial for improving current treatment status and patient outcomes. Our findings show that knockdown of NCAPH suppresses cell proliferation, migration, and xenograft tumor growth, while enhancing radiotherapy-induced cellular apoptosis. Importantly, we found that NCAPH binds to PD-L1 and disrupts its degradation, competing with HIP1R (Huntingtin-interacting protein 1-related) and leading to the stabilization of PD-L1 protein, which contributes to the formation of immunosuppressive tumor microenvironment. To inhibit the interaction between NCAPH and PD-L1, we created a peptide known as NPIDP (NCAPH and PD-L1 Interaction Disrupting Peptide) that effectively disrupts the interaction between NCAPH and PD-L1. Furthermore, topotecan, a well-characterized topoisomerase I inhibitor, was identified to bind NCAPH and promote its proteasomal degradation. Notably, we demonstrated that NPIDP and topotecan suppress tumor immune evasion both in vitro and in vivo. In summary, our findings reveal the critical role of NCAPH in regulating tumor immune surveillance, suggesting that NCAPH could serve as a potential biomarker and therapeutic target for HNSCC in the future.
{"title":"NCAPH promotes immune evasion via inhibiting PD-L1 protein degradation in head and neck squamous cell carcinoma","authors":"Baiyang Liu , Xudong Xiang , Yan Cheng , Jimin Fei , Mengge Wu , Laihao Qu , Xian Zhao , Xing Chen , Yao Li , Jia Du , Dengcai Mu , Haoqing Zhai , Qiushuo Shen , Yongbin Chen , Cuiping Yang","doi":"10.1016/j.canlet.2025.218218","DOIUrl":"10.1016/j.canlet.2025.218218","url":null,"abstract":"<div><div>Head and neck squamous cell carcinoma (HNSCC) is an epithelial carcinoma characterized by its distinct geographical distribution, exhibiting a higher prevalence in Southeast Asia. Despite the approval of immune checkpoint blockade (ICB) therapy for treating advanced recurrent HNSCC, the extent of patient benefit remains limited. Elucidating the molecular regulatory mechanisms of immunosuppressive tumor microenvironment in HNSCC is crucial for improving current treatment status and patient outcomes. Our findings show that knockdown of NCAPH suppresses cell proliferation, migration, and xenograft tumor growth, while enhancing radiotherapy-induced cellular apoptosis. Importantly, we found that NCAPH binds to PD-L1 and disrupts its degradation, competing with HIP1R (Huntingtin-interacting protein 1-related) and leading to the stabilization of PD-L1 protein, which contributes to the formation of immunosuppressive tumor microenvironment. To inhibit the interaction between NCAPH and PD-L1, we created a peptide known as NPIDP (NCAPH and PD-L1 Interaction Disrupting Peptide) that effectively disrupts the interaction between NCAPH and PD-L1. Furthermore, topotecan, a well-characterized topoisomerase I inhibitor, was identified to bind NCAPH and promote its proteasomal degradation. Notably, we demonstrated that NPIDP and topotecan suppress tumor immune evasion both in vitro and in vivo. In summary, our findings reveal the critical role of NCAPH in regulating tumor immune surveillance, suggesting that NCAPH could serve as a potential biomarker and therapeutic target for HNSCC in the future.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218218"},"PeriodicalIF":10.1,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741333","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 : 2025-12-10DOI: 10.1016/j.canlet.2025.218191
Yuan Gao , Lee X. Li , Andrew Rowland , Christos S. Karapetis , Natalie Parent , Ganessan Kichenadasse , Ashley M. Hopkins , Michael J. Sorich
{"title":"Progressive lesion type is predictive of post-progression survival in first-line chemoimmunotherapy for Non-Small Cell Lung Cancer","authors":"Yuan Gao , Lee X. Li , Andrew Rowland , Christos S. Karapetis , Natalie Parent , Ganessan Kichenadasse , Ashley M. Hopkins , Michael J. Sorich","doi":"10.1016/j.canlet.2025.218191","DOIUrl":"10.1016/j.canlet.2025.218191","url":null,"abstract":"","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218191"},"PeriodicalIF":10.1,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741323","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 : 2025-12-09DOI: 10.1016/j.canlet.2025.218214
Seunghyun Kang , Donghyeok Seol , Jieun Lee , Chanmi Bang , Mira Yoo , Soyeon Kim , Sepil An , Hyeongjin Cho , Duyeong Hwang , So Hyun Kang , Young Suk Park , Sang-Hoon Ahn , Hyung-Ho Kim , Eunhee Yi , Sanghyun Kim , Yun-Suhk Suh , Hoon Kim
Gastric cancer (GC) is characterized by marked molecular heterogeneity that contributes to differential patient outcomes. Focal amplification in form of extrachromosomal DNA (ecDNA) is common in multiple cancer types and is associated with poor patient outcomes, but its prevalence and clinical implications in GC remain largely unclear. In this study, we analyzed whole genome and whole transcriptome sequencing from 76 GC patients collected at a single hospital (Seoul National University Bundang Hospital) in Korea. EcDNAs were detected in 22.4 % (n = 17) of GC patients. Notably, 75.0 % (n = 12) of the patients in the ‘chromosomal instability (CIN)’ category carried ecDNAs which frequently co-occurred with chromothripsis. We found that ecDNAs were enriched for known cancer genes, and the presence of ecDNAs was associated with poor patient prognosis. Among the CIN cases, patients carrying ecDNAs showed gene expression patterns related to chromosomal instability, as also observed in patients having only non-ecDNA chromosomal amplicons (ChAmp) but exhibited more pronounced immune suppression. Our findings show that ecDNAs display distinct molecular characteristics in GC, including the high prevalence of cancer genes and pronounced characteristic of immune suppression, alongside clinical implications, suggesting that ecDNA is a key molecular factor in the clinical management of GC patients, particularly for the CIN subtype patients.
{"title":"Extrachromosomal DNA amplifications exhibit distinct molecular characteristics and prognostic implications in gastric cancer","authors":"Seunghyun Kang , Donghyeok Seol , Jieun Lee , Chanmi Bang , Mira Yoo , Soyeon Kim , Sepil An , Hyeongjin Cho , Duyeong Hwang , So Hyun Kang , Young Suk Park , Sang-Hoon Ahn , Hyung-Ho Kim , Eunhee Yi , Sanghyun Kim , Yun-Suhk Suh , Hoon Kim","doi":"10.1016/j.canlet.2025.218214","DOIUrl":"10.1016/j.canlet.2025.218214","url":null,"abstract":"<div><div>Gastric cancer (GC) is characterized by marked molecular heterogeneity that contributes to differential patient outcomes. Focal amplification in form of extrachromosomal DNA (ecDNA) is common in multiple cancer types and is associated with poor patient outcomes, but its prevalence and clinical implications in GC remain largely unclear. In this study, we analyzed whole genome and whole transcriptome sequencing from 76 GC patients collected at a single hospital (Seoul National University Bundang Hospital) in Korea. EcDNAs were detected in 22.4 % (n = 17) of GC patients. Notably, 75.0 % (n = 12) of the patients in the ‘chromosomal instability (CIN)’ category carried ecDNAs which frequently co-occurred with chromothripsis. We found that ecDNAs were enriched for known cancer genes, and the presence of ecDNAs was associated with poor patient prognosis. Among the CIN cases, patients carrying ecDNAs showed gene expression patterns related to chromosomal instability, as also observed in patients having only non-ecDNA chromosomal amplicons (ChAmp) but exhibited more pronounced immune suppression. Our findings show that ecDNAs display distinct molecular characteristics in GC, including the high prevalence of cancer genes and pronounced characteristic of immune suppression, alongside clinical implications, suggesting that ecDNA is a key molecular factor in the clinical management of GC patients, particularly for the CIN subtype patients.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218214"},"PeriodicalIF":10.1,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741202","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 : 2025-12-09DOI: 10.1016/j.canlet.2025.218204
Yupeng Guan , Fei Cao , Yusheng Luo , Jun Li , Peng Wu , Junfu Zhang , Wenhan Qiu , Shaohong Lai , Hanqi Lei , Jun Pang
High-fat diet (HFD) and obesity are established risk factors for therqpy resistance in prostate cancer (PCa), but the underlying mechanisms remain incompletely understood. Here, we demonstrate that a HFD promote chemoresistance by remodeling the tumor microenvironment (TME) and activating extracellular matrix (ECM)-dependent mitochondria-endoplasmic reticulum contacts (MERCs). Through integration of clinical data with multi-omics and biomechanical analyses, we show that lipid-overloaded tumor cells secrete TGF-β1 to indirectly drive the activation of cancer-associated fibroblasts (CAFs). This triggers pathological ECM stiffening and collagen deposition. These biomechanical alterations are sensed by the mechanosensor Piezo1, which transduces pro-malignant signals that foster chemoresistance. Pharmacological inhibition of Piezo1 blocks its channel activity, disrupts intracellular ion homeostasis and consequently induces MERCs dissociation. MERCs disassembly, in return, destabilizes the IP3R-GRP75-VDAC complex, leading to metabolic reprogramming characterized by mitochondrial dysfunction, endoplasmic reticulum stress, and redox imbalance. Crucially, dual targeting of lipid metabolism (with statins) and mechanotransduction (with GsMTx4) resensitizes PCa to chemotherapy by normalizing ECM architecture and restoring MERCs integrity. Our work defines the "mechanometabolic niche" as a targetable signaling hub where coordinated lipid metabolism and TME biomechanics converge to dictate therapeutic response and unveils a novel co-targeting strategy for advanced PCa.
{"title":"High-fat diet induced ECM remodeling attenuates chemosensitivity in prostate cancer via activating Piezo1-dependent mitochondria-ER contacts","authors":"Yupeng Guan , Fei Cao , Yusheng Luo , Jun Li , Peng Wu , Junfu Zhang , Wenhan Qiu , Shaohong Lai , Hanqi Lei , Jun Pang","doi":"10.1016/j.canlet.2025.218204","DOIUrl":"10.1016/j.canlet.2025.218204","url":null,"abstract":"<div><div>High-fat diet (HFD) and obesity are established risk factors for therqpy resistance in prostate cancer (PCa), but the underlying mechanisms remain incompletely understood. Here, we demonstrate that a HFD promote chemoresistance by remodeling the tumor microenvironment (TME) and activating extracellular matrix (ECM)-dependent mitochondria-endoplasmic reticulum contacts (MERCs). Through integration of clinical data with multi-omics and biomechanical analyses, we show that lipid-overloaded tumor cells secrete TGF-β1 to indirectly drive the activation of cancer-associated fibroblasts (CAFs). This triggers pathological ECM stiffening and collagen deposition. These biomechanical alterations are sensed by the mechanosensor Piezo1, which transduces pro-malignant signals that foster chemoresistance. Pharmacological inhibition of Piezo1 blocks its channel activity, disrupts intracellular ion homeostasis and consequently induces MERCs dissociation. MERCs disassembly, in return, destabilizes the IP3R-GRP75-VDAC complex, leading to metabolic reprogramming characterized by mitochondrial dysfunction, endoplasmic reticulum stress, and redox imbalance. Crucially, dual targeting of lipid metabolism (with statins) and mechanotransduction (with GsMTx4) resensitizes PCa to chemotherapy by normalizing ECM architecture and restoring MERCs integrity. Our work defines the \"mechanometabolic niche\" as a targetable signaling hub where coordinated lipid metabolism and TME biomechanics converge to dictate therapeutic response and unveils a novel co-targeting strategy for advanced PCa.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218204"},"PeriodicalIF":10.1,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741171","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 : 2025-12-09DOI: 10.1016/j.canlet.2025.218216
Clara Bayona , Teodora Ranđelović , Ignacio Ochoa
Glioblastoma (GBM), the most aggressive and lethal primary brain tumor, is characterized by profound intratumoral heterogeneity and a hostile tumor microenvironment (TME) that drives immune evasion, therapeutic resistance, and relentless progression. Among its defining pathological features is the development of a hypoxic–necrotic core, long recognized as a hallmark of poor clinical outcome. This review synthesizes current insights into how hypoxia and necrosis act not merely as pathological markers, but as a spatiotemporal evolution engine of the GBM TME, driving metabolic adaptation, extracellular matrix (ECM) remodeling, and immune evasion. We examine how oxygen and nutrient deprivation activate hypoxia-inducible factors (HIFs), triggering cascades that promote angiogenesis, altered metabolism, and accumulation of immunosuppressive metabolites. These stressors also contribute to the recruitment and polarization of tumor-associated macrophages (TAMs) and neutrophils (TANs), expansion of myeloid-derived suppressor cells (MDSCs), and infiltration of regulatory T cells (Tregs), collectively creating an immune-excluded niche. Furthermore, hypoxia-induced ECM stiffening and degradation enhance tumor invasiveness while limiting immune cell access. By exploring the dynamic interplay between physicochemical stressors and immune modulation within the necrotic core, this review highlights the need for targeting the hypoxia-necrosis axis to overcome current therapeutic limitations. A deeper understanding of these processes will be crucial for the development of precision-targeted therapies in this highly refractory malignancy.
{"title":"Tumor microenvironment in glioblastoma: The central role of the hypoxic–necrotic core","authors":"Clara Bayona , Teodora Ranđelović , Ignacio Ochoa","doi":"10.1016/j.canlet.2025.218216","DOIUrl":"10.1016/j.canlet.2025.218216","url":null,"abstract":"<div><div>Glioblastoma (GBM), the most aggressive and lethal primary brain tumor, is characterized by profound intratumoral heterogeneity and a hostile tumor microenvironment (TME) that drives immune evasion, therapeutic resistance, and relentless progression. Among its defining pathological features is the development of a hypoxic–necrotic core, long recognized as a hallmark of poor clinical outcome. This review synthesizes current insights into how hypoxia and necrosis act not merely as pathological markers, but as a spatiotemporal evolution engine of the GBM TME, driving metabolic adaptation, extracellular matrix (ECM) remodeling, and immune evasion. We examine how oxygen and nutrient deprivation activate hypoxia-inducible factors (HIFs), triggering cascades that promote angiogenesis, altered metabolism, and accumulation of immunosuppressive metabolites. These stressors also contribute to the recruitment and polarization of tumor-associated macrophages (TAMs) and neutrophils (TANs), expansion of myeloid-derived suppressor cells (MDSCs), and infiltration of regulatory T cells (Tregs), collectively creating an immune-excluded niche. Furthermore, hypoxia-induced ECM stiffening and degradation enhance tumor invasiveness while limiting immune cell access. By exploring the dynamic interplay between physicochemical stressors and immune modulation within the necrotic core, this review highlights the need for targeting the hypoxia-necrosis axis to overcome current therapeutic limitations. A deeper understanding of these processes will be crucial for the development of precision-targeted therapies in this highly refractory malignancy.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218216"},"PeriodicalIF":10.1,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741268","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 : 2025-12-09DOI: 10.1016/j.canlet.2025.218211
Zhou Qi , Yinian Zhang , Ye Gong , Chen Liang , Qingping Zhang , Yaling Chen , Mingrui Zhao , Binbin Zhang , Zhiyong Liu , Beichen Zhang , Jian Li , Jianli Liu , Yawen Pan , Shiwen Guo
Glioblastoma (GBM) is a highly invasive and treatment-resistant brain tumour, with recurrence often driven by the persistence of brain tumour stem cells (BTSCs). Recent evidence suggests that BTSC-derived exosomes, particularly under hypoxic conditions, play a critical role in GBM progression by facilitating intercellular communication and enhancing tumour invasiveness; however, the precise molecular mechanisms remain unclear. We demonstrated that hypoxic BTSCs (H-BTSCs) influence glioma cells through the transfer of exosomes. High-throughput sequencing revealed a marked increase in miR-151a-3p expression under hypoxic. Mechanistically, miR-151a-3p functions within a nuclear-activating miRNA (NamiRNA)-enhancer network: P300 acetylates PDE4D, and H3K27ac-dependent binding to the PDE4D promoter upregulates Focal Adhesion Kinase (FAK)/Yes-Associated Protein (YAP) signaling in GBM cells. CRISPR/Cas9-mediated deletion of the PDE4D enhancer confirmed that miR-151a-3p's function is enhancer dependent. Both in vitro and in vivo experiments demonstrated that exosomal miR-151a-3p promotes glioma cell migration, invasion, proliferation, and epithelial‒mesenchymal transition, thereby increasing tumour aggressiveness. These findings highlight the NamiR-151a-3p/PDE4D/FAK/YAP axis as a promising therapeutic target for GBM.
{"title":"BTSCs exosomes derived NamiRNA-enhancer network of miR-151a-3p mediates a positive feedback loop and promotes the progression of glioma via FAK phosphorylation","authors":"Zhou Qi , Yinian Zhang , Ye Gong , Chen Liang , Qingping Zhang , Yaling Chen , Mingrui Zhao , Binbin Zhang , Zhiyong Liu , Beichen Zhang , Jian Li , Jianli Liu , Yawen Pan , Shiwen Guo","doi":"10.1016/j.canlet.2025.218211","DOIUrl":"10.1016/j.canlet.2025.218211","url":null,"abstract":"<div><div>Glioblastoma (GBM) is a highly invasive and treatment-resistant brain tumour, with recurrence often driven by the persistence of brain tumour stem cells (BTSCs). Recent evidence suggests that BTSC-derived exosomes, particularly under hypoxic conditions, play a critical role in GBM progression by facilitating intercellular communication and enhancing tumour invasiveness; however, the precise molecular mechanisms remain unclear. We demonstrated that hypoxic BTSCs (H-BTSCs) influence glioma cells through the transfer of exosomes. High-throughput sequencing revealed a marked increase in miR-151a-3p expression under hypoxic. Mechanistically, miR-151a-3p functions within a nuclear-activating miRNA (NamiRNA)-enhancer network: P300 acetylates PDE4D, and H3K27ac-dependent binding to the PDE4D promoter upregulates Focal Adhesion Kinase (FAK)/Yes-Associated Protein (YAP) signaling in GBM cells. CRISPR/Cas9-mediated deletion of the PDE4D enhancer confirmed that miR-151a-3p's function is enhancer dependent. Both <em>in vitro</em> and <em>in vivo</em> experiments demonstrated that exosomal miR-151a-3p promotes glioma cell migration, invasion, proliferation, and epithelial‒mesenchymal transition, thereby increasing tumour aggressiveness. These findings highlight the NamiR-151a-3p/PDE4D/FAK/YAP axis as a promising therapeutic target for GBM.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218211"},"PeriodicalIF":10.1,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741271","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 : 2025-12-09DOI: 10.1016/j.canlet.2025.218215
Sheng Zhang , Yining Jin , Zhiliang Jia , Xueqing Xia , Yang Li , Qi Wang , Jing Wang , Jian Wang , Joya Chandra , Gregory K. Friedman , Shulin Li
The failure to prevent brain tumors, including both recurrent primary and metastatic brain tumors, is the primary cause of patients’ mortality. We developed a novel whole tumor-cell vaccine to rapidly induce long-duration brain-resident memory T (TRM) cells that prevent brain tumor progression. Ten Fgl2-KO primary and metastatic tumor cell lines, generated via CRISPR/Cas9, were used to vaccinate mice and for intracranial challenges with the WT tumor cells. Not only did vaccinated mice reject these tumor cell challenges, but also more than half of these mice became long-duration survivors. Transplanting brain immune cells from vaccinated mice into naïve mice enabled this rejection of intracranial challenges in the recipient mice, whereas depleting TRM cells impaired it. Mechanistic studies uncovered that Fgl2 KO impaired the immunosuppressive molecule CD47; reconstitution of CD47 expression in Fgl2-KO tumor cells reversed the protection. Likewise, vaccination with CD47-knockdown tumor cells produced similar effects. Proteomic analysis found that Fgl2-KO–mediated suppression of CD47 occurred through the Src and PKCα pathways; inhibition of either pathway reduced CD47 expression. This study is the first to show that disrupting the Fgl2-CD47 circuit in tumor cells impairs their tumorigenic properties and induces long-term brain TRM cells, thereby providing new strategies for improving the efficacy of currently used whole tumor-cell vaccines.
{"title":"Fgl2-knockout tumor cells serve as a vaccine inducing long-duration brain-resident memory T cells that reject subsequent intracranial tumor cell challenges","authors":"Sheng Zhang , Yining Jin , Zhiliang Jia , Xueqing Xia , Yang Li , Qi Wang , Jing Wang , Jian Wang , Joya Chandra , Gregory K. Friedman , Shulin Li","doi":"10.1016/j.canlet.2025.218215","DOIUrl":"10.1016/j.canlet.2025.218215","url":null,"abstract":"<div><div>The failure to prevent brain tumors, including both recurrent primary and metastatic brain tumors, is the primary cause of patients’ mortality. We developed a novel whole tumor-cell vaccine to rapidly induce long-duration brain-resident memory T (T<sub>RM</sub>) cells that prevent brain tumor progression. Ten Fgl2-KO primary and metastatic tumor cell lines, generated via CRISPR/Cas9, were used to vaccinate mice and for intracranial challenges with the WT tumor cells. Not only did vaccinated mice reject these tumor cell challenges, but also more than half of these mice became long-duration survivors. Transplanting brain immune cells from vaccinated mice into naïve mice enabled this rejection of intracranial challenges in the recipient mice, whereas depleting T<sub>RM</sub> cells impaired it. Mechanistic studies uncovered that Fgl2 KO impaired the immunosuppressive molecule CD47; reconstitution of CD47 expression in Fgl2-KO tumor cells reversed the protection. Likewise, vaccination with CD47-knockdown tumor cells produced similar effects. Proteomic analysis found that Fgl2-KO–mediated suppression of CD47 occurred through the Src and PKCα pathways; inhibition of either pathway reduced CD47 expression. This study is the first to show that disrupting the Fgl2-CD47 circuit in tumor cells impairs their tumorigenic properties and induces long-term brain T<sub>RM</sub> cells, thereby providing new strategies for improving the efficacy of currently used whole tumor-cell vaccines.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"640 ","pages":"Article 218215"},"PeriodicalIF":10.1,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741179","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.2025.218213
Yuanxin Zhu , Wenjia Li , Yuntan Qiu , Zhihuai Deng , Yu Li , Hengxing Chen , Jingyuan Zhang , Daning Lu , Kaishun Hu , Dongsheng Huang , Dong Yin
Osteosarcoma is a primary malignant bone tumour with an unsatisfactory prognosis, and individualised and comprehensive treatment is needed. HP1 (α/β/γ) is an important heterochromatin protein involved in transcriptional regulation and is also involved in the DNA damage response (DDR). However, little is known about the participation of HP1 in DNA damage-induced transcriptional repression. In this study, HP1 proteins were shown to be involved in DNA damage-mediated transcriptional repression at the very onset of DNA damage. Mechanistically, HP1 proteins were recruited to DNA damage sites by interacting with and being covalently PARylated by PARP1. This process increased H2AK119Ub, which ultimately led to the inactivation of RNA Pol II to achieve transcriptional suppression. Silencing HP1 led to a weakening of PARP1 recruitment and homologous recombination (HR) repair. Concurrently, HP1γ (CBX3) knockdown resulted in an increased the sensitivity of osteosarcoma cells to radiotherapy, chemotherapy and PARP1 inhibitors. The results of the study demonstrated the involvement of HP1 in the DDR via covalent PARylation by PARP1, resulting in the suppression of transcription and the promotion of HR repair. Overall, these results identify a new molecular mechanism of DNA damage-induced transcriptional repression and provide a theoretical basis for the potential application of DNA damage-induced transcriptional repression in the treatment of osteosarcoma.
骨肉瘤是一种预后不佳的原发性恶性骨肿瘤，需要个体化和综合治疗。HP1 （α/β/γ）是参与转录调控的重要异染色质蛋白，也参与DNA损伤反应（DDR）。然而，关于HP1参与DNA损伤诱导的转录抑制知之甚少。在这项研究中，HP1蛋白被证明在DNA损伤开始时参与DNA损伤介导的转录抑制。机制上，HP1蛋白通过与PARP1相互作用并被PARP1共价聚合而被招募到DNA损伤位点。这一过程增加H2AK119Ub，最终导致RNA Pol II失活，从而实现转录抑制。沉默HP1导致PARP1募集和同源重组（HR）修复的减弱。同时，HP1γ (CBX3)敲低导致骨肉瘤细胞对放疗、化疗和PARP1抑制剂的敏感性增加。研究结果表明，HP1通过PARP1的共价PARylation参与DDR，从而抑制转录并促进HR修复。总的来说，这些结果确定了DNA损伤诱导的转录抑制的新的分子机制，并为DNA损伤诱导的转录抑制在骨肉瘤治疗中的潜在应用提供了理论基础。
{"title":"HP1 enhances radio- and chemotherapy resistance in osteosarcoma via PARP1-dependent transcriptional repression and HR repair","authors":"Yuanxin Zhu , Wenjia Li , Yuntan Qiu , Zhihuai Deng , Yu Li , Hengxing Chen , Jingyuan Zhang , Daning Lu , Kaishun Hu , Dongsheng Huang , Dong Yin","doi":"10.1016/j.canlet.2025.218213","DOIUrl":"10.1016/j.canlet.2025.218213","url":null,"abstract":"<div><div>Osteosarcoma is a primary malignant bone tumour with an unsatisfactory prognosis, and individualised and comprehensive treatment is needed. HP1 (α/β/γ) is an important heterochromatin protein involved in transcriptional regulation and is also involved in the DNA damage response (DDR). However, little is known about the participation of HP1 in DNA damage-induced transcriptional repression. In this study, HP1 proteins were shown to be involved in DNA damage-mediated transcriptional repression at the very onset of DNA damage. Mechanistically, HP1 proteins were recruited to DNA damage sites by interacting with and being covalently PARylated by PARP1. This process increased H2AK119Ub, which ultimately led to the inactivation of RNA Pol II to achieve transcriptional suppression. Silencing HP1 led to a weakening of PARP1 recruitment and homologous recombination (HR) repair. Concurrently, HP1γ (CBX3) knockdown resulted in an increased the sensitivity of osteosarcoma cells to radiotherapy, chemotherapy and PARP1 inhibitors. The results of the study demonstrated the involvement of HP1 in the DDR via covalent PARylation by PARP1, resulting in the suppression of transcription and the promotion of HR repair. Overall, these results identify a new molecular mechanism of DNA damage-induced transcriptional repression and provide a theoretical basis for the potential application of DNA damage-induced transcriptional repression in the treatment of osteosarcoma.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"639 ","pages":"Article 218213"},"PeriodicalIF":10.1,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145721084","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.2025.218209
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.
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