Cancer Communications最新文献

{"title":"CEBPB-Regulated Gastric Cell Plasticity Promotes Liver Metastasis of Gastric Cancer.","authors":"Zhixiang Zuo, Jiaqi Liang, Li-Na He, Kai Xu, Muren Hu, Kunming Zhang, Wei Gao, Junyi Yin, Lanlin Zhang, Boning Ma, Zhiqian Hu, Pengfei Zhang, Hong Jiang","doi":"10.34133/cancomm.0016","DOIUrl":"https://doi.org/10.34133/cancomm.0016","url":null,"abstract":"<p><p><b>Background:</b> Liver metastasis represents the most common distant dissemination in gastric cancer (GC) but persists as a challenging condition to manage, and its driving molecular mechanisms remain poorly understood. This study aimed to uncover the key regulatory drivers of GC liver metastasis and explore their potential as therapeutic targets. <b>Methods:</b> Herein, we employed a multifaceted approach combining single-cell RNA sequencing, bulk transcriptomics, epigenomics analyses of GC primary tumors and normal adjacent tissues, paired liver metastasis, and circulating tumor cells, alongside in vitro and in vivo experimental validation, to investigate how metastatic GC cells spread to and adapt within the liver microenvironment. <b>Results:</b> We discovered that GC cells undergoing liver metastasis transcriptionally reprogrammed into a high plasticity state. This plasticity was mediated by the transcription factor CCAAT enhancer-binding protein beta (<i>CEBPB</i>), which activated liver metastasis-associated genes through enhancer reprogramming. Notably, <i>CEBPB</i>-driven reprogramming enhanced the metastatic potential of GC cells and enabled them to evade immune surveillance via interactions between cluster of differentiation 155 (CD155) and T cell immunoreceptor with Ig and ITIM domains (TIGIT). Blocking the CD155-TIGIT interplay inhibited liver metastasis and restored T cell cytotoxicity. <b>Conclusions:</b> Our study identifies CEBPB-mediated transcriptional and epigenetic reprogramming as a fundamental driver of GC liver metastasis. Our findings underscore the <i>CEBPB</i>/<i>CD155</i>/<i>TIGIT</i> axis as a promising therapeutic target for liver-metastatic GC.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"46 ","pages":"0016"},"PeriodicalIF":24.9,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12981248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147466872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vebreltinib for Previously Treated Astrocytoma, <i>IDH</i>-Mutant, Grade 4, and Glioblastoma, <i>IDH</i> Wild-Type with <i>PTPRZ1-MET</i> Fusion Gene: A Multicenter, Phase III Randomized, Open-Label Trial.","authors":"Zhaoshi Bao, Yake Xue, Yanhui Liu, Shouwei Li, Liang Wang, Yan Qu, Yonggao Mou, Rutong Yu, Jinsong Wu, Yu Yao, Kai Shu, Guangyuan Hu, Linbo Cai, Wenbin Li, Xiaoguang Qiu, Yunqian Li, Lei Zhang, Songtao Qi, Ying Ji, Chunxiao Ma, Wenbin Ma, Gang Li, Rongjie Tao, Chongran Sun, Ligang Chen, Sheng-Qing Lv, Peng Liang, Hao Pan, Woo Yat Ming Peter, Chan Tat Ming Danny, Qing Mao, Xinting Wei, Tao Jiang","doi":"10.34133/cancomm.0019","DOIUrl":"https://doi.org/10.34133/cancomm.0019","url":null,"abstract":"<p><p><b>Background:</b> High-grade gliomas, including isocitrate dehydrogenase (<i>IDH</i>)-mutant astrocytoma and <i>IDH</i> wild-type glioblastoma, have a poor prognosis and limited treatment options. The <i>PTPRZ1-MET</i> (<i>ZM</i>) fusion gene is a potential therapeutic target. This study evaluated vebreltinib, a highly selective, adenosine-triphosphate-competitive inhibitor of the mesenchymal-epithelial transition factor (<i>MET</i>), in patients with <i>ZM</i>-fusion-positive glioma. <b>Methods:</b> In this multicenter, open-label <i>ZM</i> FUsion GENe (FUGEN) trial, patients with previously treated astrocytoma, <i>IDH</i>-mutant, grade 4, or glioblastoma, <i>IDH</i> wild-type, harboring the <i>ZM</i> fusion were randomized in a 1:1 ratio to receive vebreltinib (300 mg orally twice daily) or control treatment (temozolomide or cisplatin plus etoposide) in 28-d cycles. The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety analyses. <b>Results:</b> Eighty-one patients (42 in the vebreltinib group and 39 in the control group) were included in the full analysis set. As of 2023 April 1, the median follow-up duration was 5.9 (range, 0.8 to 44.7) months in the vebreltinib group and 3.4 (range, 0.5 to 40.5) months in the control group. Median OS was significantly longer in the vebreltinib group than in the control group (6.3 months versus 3.4 months; hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.32 to 0.85; stratified log-rank <i>P</i> = 0.007). In the <i>IDH</i>-mutant subgroup, median OS was 7.7 months in the vebreltinib group and 3.3 months in the control group (HR, 0.48; 95% CI, 0.28 to 0.80; stratified log-rank <i>P</i> = 0.005). Among patients with a baseline tumor diameter of ≤3.0 cm, median OS was 32.5 months in the vebreltinib group versus 4.2 months in the control group (HR, 0.27; 95% CI, 0.07 to 1.06; stratified log-rank <i>P</i> = 0.046). Median PFS was also longer in the vebreltinib group (1.9 months versus 1.1 months; HR, 0.54; 95% CI, 0.33 to 0.88; stratified log-rank <i>P</i> = 0.012). The ORR was 9.5% with vebreltinib and 2.6% with control treatment. The incidence of grade ≥3 adverse events was comparable between groups, and no treatment-related deaths were reported. <b>Conclusion:</b> Vebreltinib significantly improved OS in patients with previously treated high-grade glioma harboring the <i>ZM</i> fusion, particularly in the subgroup with <i>IDH</i>-mutant astrocytoma, and the safety profile was manageable. <b>Trial registration:</b> This study was registered with the Chinese Drug Clinical Trial Registry (ChinaDrugTrials.org.cn) under the identifier, CTR20181664 (registration date: 2018 September 19).</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"46 ","pages":"0019"},"PeriodicalIF":24.9,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12976379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ectopic CD11c Drives SMAD3-Mediated Aberrant Antigen Presentation and Epithelial-Mesenchymal Transition in Esophageal Squamous Cell Carcinoma.","authors":"Han Liao, Xuan Zhao, Liping Chen, Qingyi Liu, Chenying Li, Kai Li, Yiyi Xi, Yanrong Shen, Wen Tan, Chen Wu, Dongxin Lin","doi":"10.34133/cancomm.0014","DOIUrl":"10.34133/cancomm.0014","url":null,"abstract":"<p><p><b>Background:</b> Esophageal squamous cell carcinoma (ESCC) is a highly aggressive cancer with a poor prognosis, where immune evasion plays a central role in tumor progression and resistance to therapy. The underlying mechanisms of tumor-stroma interactions remain poorly understood, despite the relationship between epithelial-mesenchymal transition (EMT) and altered immune response having been suggested. This study aimed to investigate how phenotypic shifts in ESCC tumor cells contribute to immune modulation. <b>Methods:</b> We used multiplex immunofluorescence on 4-nitroquinoline 1-oxide (4-NQO)-induced multistage mouse ESCC models to characterize the local tumor microenvironment. Additionally, we integrated multiomics datasets, including spatial transcriptomics, single-cell RNA sequencing, and proteomics, from multistage human esophageal samples to investigate the underlying molecular mechanisms. These findings were further validated through in vitro cell line experiments and in vivo therapeutic models. <b>Results:</b> We identified an ESCC cell cluster with ectopic expression of CD11c (also known as integrin alpha X), in both mice and humans, probably formed via tumor protein p53 (<i>TP53</i>) inactivation, causing cancer cells to escape immune killing and gain malignant phenotypes. CD11c impaired cancer cell antigen presentation and fostered EMT through up-regulation of mothers against decapentaplegic homolog 3 (SMAD3) phosphorylation in human ESCC cell lines. Mechanistically, CD11c activated SMAD3 to suppress costimulatory factors CD80/CD86 and augmented immunosuppressive CD4⁺ T cell responses through aberrant major histocompatibility complex class II-mediated antigen presentation. Evaluation in humanized mouse models further confirmed that CD11c overexpression in ESCC resulted in immune evasion, tumor metastasis, and resistance to anti-programmed death ligand 1 (PD-L1) therapy, but could be rescued by combined treatment with anti-phospho-SMAD3. <b>Conclusions:</b> This study reveals a mechanism by which ectopic CD11c expression causes immunosuppression and contributes to the acquisition of malignant phenotypes in ESCC. Targeting the CD11c-SMAD3 axis may enhance the efficacy of existing immunotherapies, potentially improving the treatment outcomes of ESCC patients.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"46 ","pages":"0014"},"PeriodicalIF":24.9,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12963642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147376260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness of Lung Cancer Screening by Sex and Tumor Histology: Extended, Pooled Analysis of the ITALUNG and LUSI Trials, with Comparison to Findings in the NLST.","authors":"Rudolf Kaaks, Francisco Omar Cortés-Ibáñez, Stefan Delorme, Erna Motsch, Verena Katzke, Claus-Peter Heussel, Hans-Ulrich Kauczor, Giulia Picozzi, Giuseppe Gorini, Francesca Maria Carozzi, Laura Carrozzi, Eugenio Paci, Donella Puliti, Mario Mascalchi","doi":"10.34133/cancomm.0011","DOIUrl":"https://doi.org/10.34133/cancomm.0011","url":null,"abstract":"","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"46 ","pages":"0011"},"PeriodicalIF":24.9,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12929912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147302655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>CEBPB</i> Expression in Tumor Cells Drives Immune Evasion in Colorectal Cancer via <i>CTLA4</i> Up-regulation in T Cells.","authors":"Hye Jeong Yun, Chan Ho Park, Dahye Yun, Hye-Ri Shin, Jeong Dong Lee, Changhee Park, Kiyeon Kim, Heejun Shim, Hyejin Sim, Se Min Kim, Min Jung Kim, Ji Won Park, Seung-Bum Ryoo, Yoojoo Lim, Seung-Yong Jeong, Kyu Joo Park, Tae-You Kim, Junil Kim, Jae-Kyung Won, Sae-Won Han","doi":"10.34133/cancomm.0013","DOIUrl":"10.34133/cancomm.0013","url":null,"abstract":"<p><p><b>Background:</b> Immune checkpoint inhibitors are ineffective in the majority of colorectal cancers (CRCs) that are microsatellite stable. However, the underlying reasons for their unresponsiveness and mechanisms of immune evasion are poorly understood. In the present study, we aimed to elucidate the mechanisms underlying the immune evasion driven by CRC cells. <b>Methods:</b> We performed single-cell RNA sequencing of tumor tissues from 30 CRC patients and syngeneic mice implanted with transformation-related protein 53 (<i>Trp53</i>) knockout CT26 cells. Gene expression and correlations of individual tumor microenvironment (TME) components were analyzed, and their functional significance was investigated using syngeneic mouse models and cell line co-culture experiments. <b>Results:</b> CCAAT enhancer-binding protein beta (<i>CEBPB</i>) expression was increased in tumor protein 53 (<i>TP53</i>)-mutated CRCs. We confirmed that wild-type <i>TP53</i> negatively regulated <i>CEBPB</i> expression in CRC cell lines. <i>CEBPB</i> expression was associated with decreased intratumoral T cell infiltration and negatively impacted survival in CRC patients. In the intercellular correlation analysis of gene expression, tumor epithelial cell <i>CEBPB</i> expression was significantly correlated with cytotoxic T-lymphocyte associated protein 4 (<i>CTLA4</i>) expression in T cells, especially in regulatory and exhausted T cells. <i>Cebpb</i> overexpression promoted tumor growth in the immunocompetent syngeneic mouse models, which was accompanied by increased CTLA-4 expression in tumor-infiltrating CD4⁺ T cells. In vitro co-culture experiments also showed that tumor cell <i>CEBPB</i> overexpression increased <i>CTLA4</i> in T cells. <b>Conclusions:</b> Tumor cell <i>CEBPB</i> expression, up-regulated by <i>TP53</i> mutation, can increase <i>CTLA4</i> expression in T cells and negatively affect patient outcomes. These findings suggested a central role of tumor cell <i>CEBPB</i> in shaping an immunosuppressive TME.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"46 ","pages":"0013"},"PeriodicalIF":24.9,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12929812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147302643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WTAP-Mediated Glutaminase Splicing Bias Suppresses Ferroptosis in Hepatocellular Carcinoma.","authors":"Can Zhu, Ke Wu, Tong Wu, Jun Ma, Bo Ding, Nan Jiang, Keyi Du, Guomin Ju, Haiyang Xie, Chuanhui Peng, Jian Wu, Shusen Zheng","doi":"10.34133/cancomm.0005","DOIUrl":"https://doi.org/10.34133/cancomm.0005","url":null,"abstract":"<p><p><b>Background:</b> Hepatocellular carcinoma (HCC), a highly aggressive malignancy with poor prognosis, is characterized by hyperactivation of the epidermal growth factor receptor (EGFR) signaling pathway. Glutaminase (GLS) is commonly overexpressed in numerous malignant tumors and acts as an oncogene to support cell growth and tumor progression, making it a target for cancer treatment. This study aimed to elucidate the underlying mechanisms of EGFR activation in driving glutaminolysis reprogramming and conferring ferroptosis resistance in HCC. <b>Methods:</b> Untargeted metabolomics, stable isotope-assisted metabolomic analysis, and RNA sequencing analysis were utilized to elucidate the mechanisms underlying glutaminolysis reprogramming upon EGFR activation. Immunoprecipitation, RNA pulldown, and dual-luciferase reporter assays were employed to examine the regulatory role of Wilms' tumor 1-associated protein (WTAP) phosphorylation in <i>GLS</i> alternative splicing. Flow cytometry, cell viability assays, tumor-bearing mouse models, and HCC clinical specimens were used to validate the role of the AKT-WTAP-GLS axis in ferroptosis resistance and tumor progression. <b>Results:</b> Here, we demonstrated that AKT activated by EGFR signaling phosphorylated WTAP S176 and increased WTAP binding to methyltransferase-like protein 3. The enhanced interaction promoted the site-specific N6-methyladenosine (m⁶A) modification of GLS pre-mRNA, which in turn favored the alternative splicing of <i>GLS</i> toward glutaminase C (GAC) over kidney-type glutaminase. This switch led to increased glutamine utilization and glutathione/nicotinamide adenine dinucleotide phosphate (reduced form) biosynthesis, thereby alleviating ferroptosis and promoting tumor growth in mice. In addition, the levels of WTAP pS176 and GAC expression, which were mutually correlated, were positively associated with poor prognosis of patients with HCC. <b>Conclusions:</b> These findings uncover a critical mechanism by which tumor cells counteract ferroptosis by WTAP-mediated <i>GLS</i> alternative splicing under EGFR activation, highlighting the therapeutic potential of targeting the m⁶A-dependent GLS isoform switch in HCC and offering a rationale for the development of combination therapies.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"46 ","pages":"0005"},"PeriodicalIF":24.9,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12917114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147269771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiplexed CRISPR/Cas9 Editing of Tumor Suppressor Genes in the Mouse Endometrium Recapitulates High-Risk Endometrial Carcinoma.","authors":"Maria Vidal-Sabanés, Raúl Navaridas, Núria Bonifaci, Ada Gay-Rua, Damià Ortega-Peinado, Joaquim Egea, Mario Encinas, Xavier Matias-Guiu, David Llobet-Navas, Xavier Dolcet","doi":"10.34133/cancomm.0010","DOIUrl":"10.34133/cancomm.0010","url":null,"abstract":"","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"46 ","pages":"0010"},"PeriodicalIF":24.9,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12876560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146141107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TIMELESS Promotes LUAD Growth via Suppressing Transferrin-Mediated Ferroptosis and Reprograms the Tumor Microenvironment against Anti-PD-1 Immunotherapy.","authors":"Chenchen Hu, Feiming Hu, Changjian Shao, Yuanli He, Liping Su, Daimei Shi, Lingying Yu, Yuanjie Sun, Jing Wang, Xiyang Zhang, Hongtao Duan, Junqi Zhang, Yubo Sun, Dongbo Jiang, Xiaolong Yan, Shuya Yang, Kun Yang","doi":"10.34133/cancomm.0009","DOIUrl":"10.34133/cancomm.0009","url":null,"abstract":"<p><p><b>Background:</b> Lung cancer remains a major global health burden. RNA-binding proteins (RBPs) play crucial roles in post-transcriptional gene regulation, and their dysregulation is frequently implicated in tumorigenesis. The present study aimed to elucidate the molecular network governed by the highly expressed RBP TIMELESS in lung adenocarcinoma (LUAD) and determine its mechanistic role in LUAD progression. <b>Methods:</b> The Cancer Genome Atlas-LUAD, Gene Expression Omnibus, and single-cell RNA sequencing datasets were analyzed to identify aberrantly expressed RBP genes. The RBP gene <i>TIMELESS</i> exhibited the most significant effect on LUAD cell death and was selected for further study. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation sequencing and RNA sequencing were employed to identify ferroptosis-related targets directly bound by TIMELESS. Molecular mechanisms underlying the TIMELESS-mediated regulation of ferroptosis in LUAD were investigated via immunoprecipitation-mass spectrometry, glutathione <i>S</i>-transferase pull-down, immunofluorescence-fluorescence in situ hybridization, RNA immunoprecipitation, poly(A)-tail, and RNA stability assays. In an orthotopic lung cancer mouse model treated with erastin (a ferroptosis inducer) and programmed cell death protein 1 (PD-1) blockade, the role of TIMELESS in therapeutic response was assessed via flow cytometry and multiplex immunofluorescence (mIF). Infiltrating immune cells in LUAD were analyzed by tissue microarrays (TMAs) via mIF. <b>Results:</b> TIMELESS significantly affected LUAD cell proliferation and death, and <i>TIMELESS</i> knockdown significantly enriched RNA-binding and ferroptosis pathways. Transferrin (TF) was identified as a direct TIMELESS target governing ferroptosis. TIMELESS was revealed to bind Ccr4-Not transcription complex subunit 3 (CNOT3) to promote TF mRNA degradation. TIMELESS depletion combined with erastin and PD-1 blockade enhances efficacy, prolongs survival, increases T cell and M1 macrophage infiltration, and reduces M2 macrophage infiltration. Further, high TIMELESS expression was inversely correlated with ferroptosis marker 4-hydroxynonenal but positively correlated with programmed cell death ligand 1 (PD-L1), reduced T cell and M1 macrophage infiltration, and increased M2 macrophage infiltration. <b>Conclusions:</b> TIMELESS recruits CNOT3 to accelerate TF mRNA degradation, thereby suppressing ferroptosis and promoting LUAD growth. These findings suggest that the TIMELESS/TF regulatory axis may be a promising therapeutic target for LUAD.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"46 ","pages":"0009"},"PeriodicalIF":24.9,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12864654/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor Microenvironment Onmyoji: Cytokines with Dual Protumor and Antitumor Roles.","authors":"Yaxuan Wang, Anqi Lin, Zaoqu Liu, Quan Cheng, Jian Zhang, Peng Luo","doi":"10.34133/cancomm.0008","DOIUrl":"10.34133/cancomm.0008","url":null,"abstract":"<p><p>Cytokines are essential components of the tumor microenvironment (TME) and play crucial roles in tumor initiation and progression. As key mediators of interactions between immune cells and tumor cells within the TME, many cytokines exhibit both protumor and antitumor properties. This complex duality, reminiscent of the balance philosophy pursued by \"Onmyoji\" in traditional Eastern philosophy, which involves observing and regulating opposing forces to achieve harmony, poses marked challenges in translating cytokine therapies from animal studies to clinical applications. More than 20 key cytokines constituting the TME primarily exert their effects through autocrine and paracrine mechanisms: on one hand, they can activate antitumor immune cells, inhibit tumor growth and metastasis, and induce tumor cell apoptosis to exert antitumor effects; on the other hand, they can also recruit abundant immunosuppressive cells, promote angiogenesis, and facilitate the formation of immunosuppressive microenvironments, thereby preventing natural killer and T cells from exerting their cytotoxic antitumor functions. During acute immune responses triggered by tumor antigens, the body typically stimulates dendritic cell maturation and antigen presentation, leading to antitumor immune responses; however, when acute inflammatory reactions are not promptly resolved, they subsequently transform into chronic inflammation, thereby promoting tumor progression and therapeutic resistance, wherein abundant inflammatory cytokines in the TME play crucial roles in this transition. Currently, the major obstacles to cytokine applications in combination immunotherapy are their poor persistence and uncontrolled toxic side effects, resulting in limited therapeutic efficacy; therefore, reducing toxicity while enhancing efficacy has become a top priority in current cytokine therapy-related research. The effectiveness of cytokines exhibits multifactorial regulation influenced by the unique features of the local TME, cytokine concentration, and the responsiveness profiles of target immune effector cells. This review summarizes current research on cytokines with dual protumor and antitumor effects, with a particular focus on the evolution and regulation of their functions during tumor progression, aiming to provide insights for the future development of personalized immunotherapy strategies targeting cytokines.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"46 ","pages":"0008"},"PeriodicalIF":24.9,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12857761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146103900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Ly6g^high Neutrophil Subset Dictates Breast Cancer Lung Metastasis via CD8⁺ T Cell Death.","authors":"Rui Wang, Xiaoqi Liu, Yixuan Hou, Shanchun Chen, Yongcan Liu, Zexiu Lu, Chao Chang, Die Meng, Jing Chen, Xiaojiang Cui, Zhengrong Shi, Xueying Wan, Manran Liu","doi":"10.34133/cancomm.0003","DOIUrl":"10.34133/cancomm.0003","url":null,"abstract":"<p><p><b>Background:</b> Lung metastasis is a leading cause of breast cancer (BC)-related mortality, driven by the immunosuppressive traits of the metastatic tumor microenvironment. However, the mechanisms underlying cell-cell crosstalk in shaping immune evasion within the metastatic niche remain poorly defined. Neutrophil extracellular traps (NETs) and their associated proteins, such as cathelicidin, have emerged as key mediators of metastatic regulation in cancer. Here, we aimed to decipher the interaction between a neutrophil subset characterized by high expression of lymphocyte antigen 6 complex locus g (Ly6g^high) and cluster of differentiation 8-positive T lymphocytes (CD8⁺ T cells), mediated via cathelicidin embedded in NETs, as well as their synergistic mechanism and cooperative role in promoting lung metastasis of BC. <b>Methods:</b> We characterized neutrophil heterogeneity and functional dynamics by performing single-cell RNA sequencing and flow cytometry on lung tissues derived from murine models of BC lung metastasis. We utilized cathelicidin-related antimicrobial peptide (<i>Cramp</i>) knockout mice to dissect the role of cathelicidin in NETs. The spatial colocalization of apoptotic CD8⁺ T cells and NETs was analyzed using multiplex immunofluorescence, and the molecular interactions were probed by protein binding assays. <b>Results:</b> Neutrophils in the lung metastatic niche were classified into 2 subsets based on the Ly6g expression: Ly6g^high and Ly6g^low neutrophils. Ly6g^low neutrophils, which were recruited in the macrometastatic stage, exhibited myeloid-derived suppressor cell-like characteristics. Notably, Ly6g^high neutrophils induced CD8⁺ T cell apoptosis through NET formation, with apoptotic CD8⁺ T cells spatially clustered within NET-rich areas. Mechanistically, NET-derived cathelicidin (Cramp in mice) directly bound to mitochondrial adenine nucleotide translocator 1 (Ant1) in CD8⁺ T cells, triggering conformational changes and complex formation with voltage-dependent anion channel 1 (Vdac1). These events resulted in the opening of the mitochondrial permeability transition pore and loss of mitochondrial membrane potential. <b>Conclusions:</b> Our study demonstrates that Ly6g^high neutrophils play a critical role in immunosuppression and immune evasion through NET-induced apoptosis of CD8⁺ T cells. These findings underscore the importance of NETs and cathelicidin in BC lung metastasis, suggesting their potential as therapeutic targets in restoring antitumor immunity and in preventing metastatic progression.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"46 ","pages":"0003"},"PeriodicalIF":24.9,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12857760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146103845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}