Cancer Communications最新文献

{"title":"m6A-modified EHD1 controls PD-L1 endosomal trafficking to modulate immune evasion and immunotherapy responses in lung adenocarcinoma","authors":"Fanglin Tian, Jian Huang, Weina Fan, Xin Li, Yuning Zhan, Kexin Zhu, Xiangyu Wang, Xin Hong, Xin Wang, Jin Ren, Ying Xing, Li Cai","doi":"10.1002/cac2.70052","DOIUrl":"10.1002/cac2.70052","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Eps15 homology domain (EHD) proteins, including EHD1 to EHD4, play vital roles in tumor progression. In this study, we aimed to investigate which specific EHD proteins, if any, are implicated in tumor immune evasion and immunotherapy response.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The immunotherapy responses of lung adenocarcinoma (LUAD) patients were predicted using tumor immune dysfunction and exclusion (TIDE) analysis. The T cell killing assay was performed by co-culturing activated T cells with LUAD cells. The function of EHD1 as a regulator of programmed death-ligand 1 (PD-L1) endocytic recycling was determined by receptor internalization assays. Methylated RNA immunoprecipitation (MeRIP) was performed to investigate N6-methyladenosine (m<sup>6</sup>A) modification of <i>EHD1</i> mRNA. The protein-protein interaction was revealed by the molecular docking analysis and validated by immunofluorescence (IF) and immunoprecipitation (IP) assays. RNA immunoprecipitation (RIP) was used to examine the interaction between YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1) and <i>EHD1</i> mRNA. The regulatory mechanism of YTHDF1 on <i>EHD1</i> was investigated through the application of m<sup>6</sup>A-binding site mutation analysis. The murine LUAD cells were employed to establish subcutaneous xenograft models within immunocompetent C57BL/6 mice to assess the immunomodulatory impact of EHD1 in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>TIDE algorithms and survival analysis identified that <i>EHD1</i> promoted LUAD immune escape. <i>EHD1</i> knockdown enhanced T cell cytotoxicity in killing LUAD cells across all effector-to-target (E/T) ratios. <i>EHD1</i> overexpression exerted the opposite effect. The molecular docking analysis revealed an interaction between EHD1 and the PD-L1 protein, verified by IF and IP. Furthermore, <i>EHD1</i> knockdown inhibited PD-L1 recycling, thereby promoting its lysosomal degradation. Disruption of the EHD1/PD-L1 interaction impaired the regulatory function of <i>EHD1</i> in tumor immune evasion. In an immune-competent mouse model, we found that <i>EHD1</i> silencing impeded tumor immune evasion and enhanced the efficacy of anti‑PD‑1 therapy. MeRIP-qPCR confirmed obvious m<sup>6</sup>A modification of <i>EHD1</i>. Further, the <i>EHD1</i> mRNA was found to bind to the YTHDF1 protein, an m<sup>6</sup>A reader. YTHDF1 overexpression up-regulated EHD1 expression by enhancing its mRNA stability in an m<sup>6</sup>A-dependent manner.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 10","pages":"1285-1308"},"PeriodicalIF":24.9,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70052","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697694","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":"Lifileucel tumor-infiltrating lymphocyte cell therapy in patients with unresectable or metastatic mucosal melanoma after disease progression on immune checkpoint inhibitors","authors":"Harriet Kluger, Götz Ulrich Grigoleit, Sajeve Thomas, Evidio Domingo-Musibay, Jason A Chesney, Miguel F Sanmamed, Theresa Medina, Mirjana Ziemer, Eric Whitman, Friedrich Graf Finckenstein, Brian Gastman, Jeffrey Chou, Xiao Wu, Giri Sulur, Rana Fiaz, Rongsu Qi, Amod A Sarnaik","doi":"10.1002/cac2.70050","DOIUrl":"10.1002/cac2.70050","url":null,"abstract":"<p>Mucosal melanoma (MM) is a rare melanoma that affects the mucous membranes of the gastrointestinal, respiratory, and genitourinary tracts [<span>1</span>]. In contrast to cutaneous melanoma (CM), MM occurs in body areas without sun exposure and is more difficult to detect, often overlooked until nodal or metastatic involvement [<span>2</span>]. The molecular profile of MM is distinct, with a lower mutational burden and higher degree of chromosomal aberrations than CM, potentially affecting treatment strategies [<span>3</span>]. Patients with MM typically receive the same immunotherapy as patients with CM and are not candidates for BRAF/MEK inhibition, an option for many patients with CM [<span>1</span>]. However, standard-of-care therapies and immune checkpoint inhibitors (ICIs) are associated with poor outcomes in patients with MM [<span>4-6</span>].</p><p>C-144-01 (NCT02360579) was a phase II multicenter, multicohort study of lifileucel autologous tumor-infiltrating lymphocyte (TIL) cell therapy in patients with advanced (unresectable or metastatic) melanoma, including MM, whose disease progressed on or after anti-programmed cell death protein-1/programmed cell death-ligand 1 (PD-1/PD-L1) therapy [<span>7</span>]. With median follow-up of 27.6 months (range, 0.2+ to 48.7 months), lifileucel demonstrated an Independent Review Committee (IRC)-assessed objective response rate (ORR) of 31.4% in heavily pretreated patients with advanced melanoma [<span>7</span>]. Lifileucel was approved by the US Food and Drug Administration in 2024 for the treatment of adults with unresectable or metastatic melanoma previously treated with a PD-1-blocking antibody, and if <i>BRAF</i> V600 mutation was positive, a BRAF inhibitor with or without a MEK inhibitor.</p><p>Herein, we report outcomes with lifileucel in patients with advanced MM in the C-144-01 study. Of 153 ICI-refractory patients who received lifileucel and were analyzed for efficacy in pooled cohorts 2 and 4, 12 (7.8%) had MM (Supplementary Figure S1) [<span>7</span>]. The median age of the patients with MM was 61.5 years and 6 (50.0%) were female (Supplementary Table S1). The median number of prior therapies was 2. Five patients (41.7%) had elevated lactate dehydrogenase. Disease burden was greater than in the overall population, with a median sum of diameters (SOD) of target lesions of 118.9 mm and a median of 6 target and nontarget lesions. Ten patients (83.3%) were primarily refractory to anti-PD-1/PD-L1 therapy. Baseline and disease characteristics for the entire study population are provided for comparison (Supplementary Table S1).</p><p>Patients with ≥1 resectable lesion underwent tumor resection, and samples were shipped to a centralized facility for the 22-day lifileucel manufacturing process (Supplementary Material and Methods). Fifteen patients with MM had tumor resection, with median total manufactured viable TIL cells of 25.90 × 10<sup>9</sup> (range, 0.04-72.00 × 10<sup>9</sup>). Three p","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 10","pages":"1229-1234"},"PeriodicalIF":24.9,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70050","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682088","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":"Stereotactic body radiotherapy plus cadonilimab (PD-1/CTLA-4 bispecific antibody) as third-line or beyond therapy for refractory solid tumors: A phase 1b study","authors":"Yao Xiao, Yuxia Wang, Jun Li, Cheng Cheng, Chunyong Song, Xin Wang, Liyuan Tao, Hongqing Zhuang","doi":"10.1002/cac2.70051","DOIUrl":"10.1002/cac2.70051","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Cadonilimab is a humanized immunoglobulin G1 bispecific antibody targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). This study aimed to evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) combined with cadonilimab in patients with advanced recurrent or refractory solid tumors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Patients with advanced solid tumors who progressed after at least two lines of systemic treatment, including immunotherapy, and were eligible for SBRT were enrolled. SBRT was administered to patients with high-burden/symptomatic lesions in combination with intravenous cadonilimab (6 mg/kg, once every 2 weeks). The primary endpoint was safety.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Sixty-three patients were enrolled from August 28, 2022, to September 14, 2023 (median follow-up: 9.1 months). The median prior treatment line was 3.0 (range 2.0-4.0). Approximately 46.0% (29/63) of patients had received prior PD-1/PD-L1 therapy, 36.5% (23/63) and 12.7% (8/63) of patients had non-small cell lung cancer and soft tissue sarcoma. Treatment-related adverse events (TRAEs) occurred in 38.1% (24/63) of patients, with grade 3 TRAEs reported in 3.2% (2/63). The most common TRAEs included pain (12.7%), elevated transaminases (12.7%), pneumonia (6.4%), fatigue (6.4%), nausea (4.8%), and fever (4.8%). The objective response rate (ORR) was 23.8% (95% confidence interval [CI], 14.0%-36.2%). The median progression-free survival (PFS) was 7.2 months (95% CI, 6.3-8.2 months), and the median overall survival (OS) was 10.0 months (95% CI, 7.7-12.4 months). The 6-month and 12-month local control rates were 98.4% and 93.0%, respectively. In a subgroup analysis of 23 non-small cell lung cancer patients, the ORR was 17.4% (95% CI, 5.0%-38.8%), the median PFS was 6.9 months (95% CI, 4.7-9.1 months), and the median OS was 9.1 months (95% CI, 7.3-10.9 months). Multivariate analysis indicated that receiving ≥6 cycles of cadonilimab and having an Eastern Cooperative Oncology Group performance status score of 0-1 were significantly associated with improved PFS and OS (<i>P</i> < 0.05).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>SBRT in combination with cadonilimab demonstrated manageable toxicity and promising efficacy in heavily pretreated patients with refractory solid tumors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial registration</h3>\u0000 \u0000 <","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 10","pages":"1235-1246"},"PeriodicalIF":24.9,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70051","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682089","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":"Targeting SPHK1 in macrophages remodels the tumor microenvironment and enhances anti-PD-1 immunotherapy efficacy in colorectal cancer liver metastasis","authors":"Yizhi Zhan, Jinsong Xu, Zhanqiao Zhang, Yating Hu, Yongsheng Li, Junying Qian, Yunyan Ling, Dehua Wu, Haijun Deng, Guoxin Li, Zhiyong Shen, Yuan Fang","doi":"10.1002/cac2.70047","DOIUrl":"10.1002/cac2.70047","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Colorectal cancer liver metastasis (CRLM) is characterized by an immunosuppressive microenvironment and a blunted response to immunotherapy. Notably, tumor-associated macrophages (TAMs) play a critical role in modulating immune responses and exhibit significant heterogeneity in CRLM. Sphingosine kinase 1 (SPHK1) serves as a pivotal kinase in maintaining the balance between ceramide and sphingosine-1-phosphate (S1P) levels. However, the effects of SPHK1 within TAMs on tumor immune evasion during CRLM remain elusive. This study aimed at investigating the role of TAM-intrinsic SPHK1 in tumor immunosuppressive microenvironment in CRLM.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>SPHK1 expression levels in TAMs were estimated by immunofluorescence and bioinformatics analysis. Several animal models were established to elucidate the role of SPHK1 in tumor immunity reprogramming in vivo. Flow cytometry, cytokine assay, and transwell assay were conducted to investigate the effects of SPHK1 in TAMs in cell-cell communication in vitro. RNA-sequencing, Western blotting, and quantitative real-time polymerase chain reaction were used to explore the molecular mechanism by which SPHK1 activated NLR family pyrin domain containing 3 (NLRP3) inflammasome in TAMs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found that SPHK1 was mainly expressed in TAMs and identified SPHK1<sup>+</sup> TAMs as associated with CRLM and diminished efficacy of immunotherapy in human patients. These SPHK1<sup>+</sup> TAMs exhibited strong immunosuppressive activities by inducing CD8<sup>+</sup> T cell exhaustion with high programmed cell death 1 (PD-1) expression via the interaction between TAMs and CRC cells. Mechanistically, SPHK1-produced S1P exerted an autocrine effect to activate NLRP3 inflammasome and interleukin 1 beta (IL-1β) release via nuclear factor-kappa B (NF-κB) and hypoxia inducible factor 1 subunit alpha (HIF-1α) signaling in TAMs. Paracrine IL-1β then upregulated the expression of monocyte chemoattractants and ADAM metallopeptidase domain 17 (ADAM17) sheddase in CRC cells, resulting in TAM infiltration and CD8<sup>+</sup> T cell dysfunction in the liver microenvironment. Furthermore, combining SPHK1-targeting treatments with anti-PD-1 therapy or radioimmunotherapy largely stalled liver metastasis and caused a significant extension of lifespan in preclinical mouse models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings highlighted the role of SPHK1 of TAMs in facilitating CRLM by promoting CD8<sup>+</sup> T cell ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 10","pages":"1203-1228"},"PeriodicalIF":24.9,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641884","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":"Global trends and epidemiological shifts in gastrointestinal cancers: insights from the past four decades.","authors":"Mengmeng Li, Sumei Cao, Rui-Hua Xu","doi":"10.1002/cac2.70017","DOIUrl":"10.1002/cac2.70017","url":null,"abstract":"<p><strong>Background: </strong>The epidemiological profiles of gastrointestinal (GI) cancers vary across countries and over time, largely reflecting variations in risk factors and screening practices. We aimed to provide an overview of the current global burden of the five major types of GI cancers and conduct an updated evaluation of the long-term trends of GI cancers.</p><p><strong>Methods: </strong>The updated numbers of new cases and deaths, and age-standardized rates (ASR), of the five GI cancers for 185 countries were sourced from the GLOBOCAN 2022, and presented by cancer site, continent, and human development index (HDI). For 43 countries, annual incidence and mortality data were obtained from the Cancer Incidence in Five Continents Plus and World Health Organization mortality databases, supplemented by the mortality data from the Disease Surveillance Points system for China. We compared the long-term trends of ASRs across countries since 1980, and estimated average annual percent changes (AAPCs) for the recent period 2003-2017.</p><p><strong>Results: </strong>In 2022, there were 4,783,391 new cases and 3,235,719 deaths from the five GI cancers, accounting for 23.9% and 33.2% of all new cancer cases and deaths worldwide, respectively. Cancers of oesophagus, stomach, and liver were more common in Asian and high HDI countries, and colorectal and pancreatic cancer in western and very high HDI countries. Downward trends were observed in almost all countries for gastric cancer and most countries for oesophageal cancer. For colorectal cancer, the most favorable and unfavorable trends were found in 10 and 19 countries respectively. The largest decreases in liver cancer burden were mainly in eastern and southeastern Asia, while increases were seen in North America, Oceania, and Northern Europe, with AAPCs of 3%∼7% for incidence and 2%∼9% for mortality during 2003-2017. Half of the included countries showed increases in pancreatic cancer burden, with the largest AAPCs in Cyprus, Thailand, India,Türkiye, France, and Belarus for incidence, and Türkiye, Thailand, and China for mortality.</p><p><strong>Conclusions: </strong>Deviating patterns were found for GI cancers worldwide. Multi-setting studies might provide insights into the underlying etiologies of these cancers, and identify areas where urgent cancer control strategies are needed.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"774-788"},"PeriodicalIF":24.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12328094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143728712","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":"Enhancing antitumor immunity through the combination of cholesterolized TLR7 agonist liposomes and radiotherapy: a role for IL-1β and the inflammasome pathway.","authors":"Xuejiao Han, Yuan Cheng, Dandan Wan, Aqu Alu, Ziqi Zhang, Zhenfei Bi, Manni Wang, Yan Tang, Weiqi Hong, Siyuan Chen, Li Chen, Yuquan Wei","doi":"10.1002/cac2.70024","DOIUrl":"10.1002/cac2.70024","url":null,"abstract":"<p><strong>Background: </strong>Radiotherapy (RT) is a key treatment modality in cancer therapy, utilizing high-energy radiation to directly kill tumor cells. Recent research has increasingly highlighted RT's potential to indirectly enhance antitumor immunity. However, this immune activation alone often fails to generate sustained systemic antitumor responses. In this study, we aimed to investigate the antitumor effects of combining cholesterolized toll-like receptor 7 (TLR7) agonist liposomes, specifically 1V209-Cho-Lip, with RT.</p><p><strong>Methods: </strong>Mouse tumor models were used to assess the impact of combining 1V209-Cho-Lip with RT on tumor progression and modification of the tumor microenvironment. In vitro, primary mouse bone marrow-derived dendritic cells (BMDCs) were utilized to investigate changes in function and the activated pathways through RNA sequencing. Additionally, we explored the role of oxidized mitochondrial DNA (ox-mtDNA) released from irradiated tumor cells as a damage-associated molecular pattern in modulating immune responses. The involvement of interleukin-1β (IL-1β) and the inflammasome pathway in the antitumor efficacy of the combined treatment was evaluated using Il-1β^-/- and cysteinyl aspartate specific proteinase 1 knockout (Casp1^-/-) mouse models.</p><p><strong>Results: </strong>The combination of 1V209-Cho-Lip and RT significantly inhibited tumor growth and induced antitumor immunity in tumor models. This combination therapy enhanced maturation, antigen presentation and IL-1β secretion of dendritic cells (DCs) in vitro. Ox-mtDNA released from irradiated tumor cells synergized with 1V209-Cho-Lip to activate the inflammasome pathway in DCs. The antitumor effect of the combined therapy was significantly reduced in Il-1β^-/- and Casp1^-/- mice.</p><p><strong>Conclusions: </strong>This study suggests that the combination of 1V209-Cho-Lip with RT might be a promising antitumor strategy and further studies are warranted to explore the clinical relevance of this combination therapy.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"794-812"},"PeriodicalIF":24.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12328097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143968093","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":"Deciphering the transcriptomic landscape of early HR⁺/HER2^- breast cancer in very young women.","authors":"Iris Garrido-Cano, Marta Tapia, Juan Carbonell, Carlos Peña, Sandra Torres-Ruiz, Anna Ágreda-Roca, Ana Lameirinhas, Cristina Tebar, Octavio Burgués, Cristina Hernando, Ana Lluch, Fara Brasó-Maristany, Aleix Prat, Begoña Bermejo, María Teresa Martínez, Juan Miguel Cejalvo","doi":"10.1002/cac2.70019","DOIUrl":"10.1002/cac2.70019","url":null,"abstract":"","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"789-793"},"PeriodicalIF":24.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12328086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980351","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":"Novel molecular mechanisms of immune evasion in hepatocellular carcinoma: NSUN2-mediated increase of SOAT2 RNA methylation.","authors":"Jinhua Jiang, Feng Liu, Dan Cui, Caixia Xu, Jiachang Chi, Tinghua Yan, Fang Guo","doi":"10.1002/cac2.70023","DOIUrl":"10.1002/cac2.70023","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is a deadly malignancy known for its ability to evade immune surveillance. NOP2/Sun RNA methyltransferase family member 2 (NSUN2), an RNA methyltransferase involved in carcinogenesis, has been associated with immune evasion and energy metabolism reprogramming. This study aimed to examine the molecular mechanisms underlying the involvement of NSUN2 in immune evasion and metabolic reprogramming of HCC.</p><p><strong>Methods: </strong>Single-cell transcriptomic sequencing was applied to examine cellular composition changes, particularly immune cell dynamics, in HCC and adjacent normal tissues. Bulk RNA-seq and proteomics identified key genes and proteins. Methylation sequencing and methylated RNA immunoprecipitation (MeRIP) were carried out to characterize the role of NSUN2 in 5-methylcytosine (m5C) modification of sterol O-acyltransferase 2 (SOAT2). Clinical samples from 30 HCC patients were analyzed using reverse transcription-quantitative polymerase chain reaction and Western blotting. Gene expression was manipulated using CRISPR/Cas9 and lentiviral vectors. In vitro co-culture models and metabolomics were used to study HCC cell-T cell interactions, energy metabolism, and immune evasion. Tumor growth in an orthotopic mouse model was monitored by bioluminescence imaging, with subsequent measurements of tumor weight, volume, and immunohistochemical staining.</p><p><strong>Results: </strong>Single-cell transcriptomic analysis identified a marked increase in malignant cells in HCC tissues. Cell communication analysis indicated that tumor cells might promote cancer progression by evading immune clearance. Multi-omics analyses identified NSUN2 as a key regulator in HCC development. MeRIP confirmed that NSUN2 facilitated the m5C modification of SOAT2. Analysis of human HCC tissue samples demonstrated pronounced upregulation of NSUN2 and SOAT2, along with elevated m5C levels in HCC tissues. In vitro experiments uncovered that NSUN2 augmented the reprogramming of energy metabolism and repressed the activity and cytotoxicity of CD8⁺ T cells, contributing to immune evasion. In vivo studies further substantiated the role of NSUN2 in fostering immune evasion and tumor formation of HCC by modulating the m5C modification of SOAT2.</p><p><strong>Conclusions: </strong>The findings highlight the critical role of NSUN2 in driving HCC progression through the regulation of m5C modification on SOAT2. These findings present potential molecular markers for HCC diagnosis and therapeutic targets for its treatment.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"846-879"},"PeriodicalIF":24.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12328098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143977337","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":"Risk of colorectal cancer and cancer-related mortality in type 2 diabetes patients treated with metformin, SGLT-2 inhibitors, or their combination.","authors":"Xianhua Mao, Ka-Shing Cheung, Jing-Tong Tan, Lung-Yi Mak, Chi-Ho Lee, Ho Ming Cheng, Rex Wan-Hin Hui, Esther Wai Yin Chan, Philip Leung-Ho Yu, Man-Fung Yuen, Wai K Leung, Wai-Kay Seto","doi":"10.1002/cac2.70028","DOIUrl":"10.1002/cac2.70028","url":null,"abstract":"","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"880-883"},"PeriodicalIF":24.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12328085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143977256","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":"Deletion of epithelial HKDC1 decelerates cellular proliferation and impairs mitochondrial function of tumorous epithelial cells thereby protecting from intestinal carcinogenesis.","authors":"Lea Järke, Saskia Weber-Stiehl, Kensuke Shima, Karlis Arturs Moors, Jerome Genth, Fenja Amrei Schuran, Lena Best, Markus Tschurtschenthaler, Burkhardt Flemer, Silke Lüschen, Christoph Röcken, Andreas Tholey, Christoph Kaleta, Jan Rupp, Philip Rosenstiel, Felix Sommer","doi":"10.1002/cac2.70022","DOIUrl":"10.1002/cac2.70022","url":null,"abstract":"","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"722-727"},"PeriodicalIF":24.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12328089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662564","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}