Cancer Communications最新文献

{"title":"Adjuvant capecitabine in combination with docetaxel and cyclophosphamide versus anthracycline plus docetaxel and cyclophosphamide regimen in women with high-risk, HER2-negative breast cancer: An open-label, randomized controlled trial.","authors":"Yu Song, Yingjiao Wang, Xi Cao, Ying Xu, Yidong Zhou, Qiang Sun, Songjie Shen","doi":"10.1002/cac2.70041","DOIUrl":"https://doi.org/10.1002/cac2.70041","url":null,"abstract":"<p><strong>Background: </strong>The standard adjuvant chemotherapy for early-stage, high-risk breast cancer includes anthracyclines and taxanes. While anthracycline-based regimens have proven effective in human epidermal growth factor receptor 2 (HER2)-positive breast cancer, their efficacy may be reduced in HER2-negative patients due to the lack of co-amplification of DNA topoisomerase IIα, the primary target of anthracyclines. This study compared the efficacy and safety of the regimen of docetaxel, anthracycline, and cyclophosphamide (TAC) versus a novel regimen consisting of docetaxel, cyclophosphamide, and capecitabine (TCX), hypothesizing that replacement of anthracycline with capecitabine could offer superior outcomes in this patient population.</p><p><strong>Methods: </strong>In this open-label, randomized controlled trial, 204 patients with pT1-3, node-positive or high-risk node-negative, HER2-negative early-stage breast cancer were enrolled between May 2011 and December 2013 (ClinicalTrials.gov: NCT01354522). Patients were randomized 2:1 to TAC (n = 136) or TCX (n = 68), with treatment administered every 21 days for six cycles. The primary endpoints were disease-free survival (DFS) and overall survival (OS); secondary endpoints included distant disease-free survival (DDFS), disease-specific survival (DSS), and adverse event (AE) rates.</p><p><strong>Results: </strong>With a median follow-up of 124.4 (range, 19.5-147.8) months, TCX did not significantly improve the 10-year DFS rate over TAC (71.5% ± 5.6% vs. 67.6% ± 4.0%, P = 0.477). However, the 10-year OS rate was significantly higher in the TCX group than in the TAC group (91.0% ± 3.5% vs. 77.2% ± 3.6%, P = 0.009). The TCX group also showed trends toward improved 10-year DDFS rate (82.0% ± 4.7% vs. 69.8% ± 3.9%, P = 0.052) and significantly higher 10-year DSS rate (93.9% ± 3.0% vs. 77.8% ± 3.6%, P = 0.002) compared to the TAC group. Grade 3-4 AEs occurred significantly more often in the TAC group than the TCX group (67.7% vs. 42.7%, P = 0.001).</p><p><strong>Conclusion: </strong>TCX may provide superior long-term survival and a more favorable safety profile compared to TAC for patients with high-risk HER2-negative breast cancer, warranting further investigation in larger cohorts.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257389","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}

{"title":"Associations of body mass index and waist circumference with incidence of overall and of 27 site-specific cancers: a population-based retrospective cohort study.","authors":"Seonghye Kim, Bongseong Kim, Kyu-Won Jung, Ga Eun Nam, Wonyoung Jung, Junhee Park, Kyung-Do Han, Dong Wook Shin","doi":"10.1002/cac2.70039","DOIUrl":"https://doi.org/10.1002/cac2.70039","url":null,"abstract":"<p><strong>Background: </strong>Overweight and obesity are known risk factors for cancer. The aim of this study was to investigate associations of body mass index (BMI) and waist circumference (WC) with incidence of 27 site-specific cancers stratified by sex and menopausal status accounting for non-linearity.</p><p><strong>Methods: </strong>We performed a population-based retrospective cohort study using the Korean National Health Insurance Service (KNHIS 2009-2020) database. We included 3,986,155 participants (aged ≥ 20 years), and the mean follow-up duration was 9.0 ± 1.6 years. The primary outcome was the incidence of cancer.</p><p><strong>Results: </strong>There were positive associations between BMI or WC and incidences of cancers including overall cancer, digestive tract cancer (except for esophageal cancer), hepato-bilio-pancreatic cancer, hematological cancer, sex-specific cancers, brain/central nervous system (postmenopausal women), thyroid, renal, and bladder cancers. We observed inverse associations for several cancers, including lung and laryngeal cancers.</p><p><strong>Conclusions: </strong>Our findings of differential associations of BMI and WC with incidence of various cancers contribute to the understanding of the relationship between obesity and cancer risk in Asian populations. These results may provide evidence to support the implementation of active surveillance and targeted management strategies for obesity.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144233284","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}

{"title":"Lipid metabolism reprograming by SREBP1-PCSK9 targeting sensitizes pancreatic cancer to immunochemotherapy.","authors":"Mengyi Lao, Xiaozhen Zhang, Zejun Li, Kang Sun, Hanshen Yang, Sicheng Wang, Lihong He, Yan Chen, Hanjia Zhang, Jiatao Shi, Daqian Xu, Tingbo Liang, Xueli Bai","doi":"10.1002/cac2.70038","DOIUrl":"https://doi.org/10.1002/cac2.70038","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic cancer's aberrant lipid metabolism fuels cell growth, invasion, and metastasis, yet its impact on immune surveillance and immunotherapy is unclear. This study investigated how sterol regulatory element-binding transcription factor 1 (SREBP1)-driven lipid metabolism affects the tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC).</p><p><strong>Methods: </strong>Clinical significance of SREBP1 was assessed in a PDAC cohort from China and The Cancer Genome Atlas (TCGA) cohorts. The in vitro mechanisms that SREBP1 regulated programmed cell death-ligand 1 (PD-L1) and proprotein convertase subtilisin/kexin type 9 (PCSK9) were investigated using immunofluorescence, flow cytometry, Western blotting, luciferase assays and chromatin immunoprecipitation. In vivo studies using PDAC-bearing mice, humanized patient-derived tumor xenograft (PDX) models, and autochthonous model of mutation (GEMM-KTC) evaluated the efficacy and mechanisms of programmed death receptor 1 (PD-1) antibodies and lipid inhibitors.</p><p><strong>Results: </strong>Patients responding to anti-PD-1 therapy exhibited lower serum lipid levels than non-responders. Targeting SREBP1 disrupted lipid metabolism, decelerated tumor growth, and boosted the efficacy of immunotherapy for PDAC. Mechanistically, SREBP1 directly bound the PD-L1 promoter, suppressing its transcription. Meanwhile, PCSK9, a direct transcriptional target of SREBP1, modulated PD-L1 levels via lysosomal degradation. Consequently, the combination of PCSK9-neutralizing antibodies with PD-1 monotherapy showed a robust antitumor effect in both humanized PDX and GEMM-KTC models.</p><p><strong>Conclusions: </strong>The SREBP1-PCSK9 axis-mediated lipid metabolism is crucial for triggering immune evasion and resistance to anti-PD-1. Targeting the SREBP1-PCSK9 axis could potentially reverse PDAC's resistance to anti-PD-1 therapy.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172965","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}

{"title":"Simvastatin overcomes the pPCK1-pLDHA-SPRINGlac axis-mediated ferroptosis and chemo-immunotherapy resistance in AKT-hyperactivated intrahepatic cholangiocarcinoma.","authors":"Jinghan Zhu, Yixiao Xiong, Yuxin Zhang, Huifang Liang, Kun Cheng, Yuanxiang Lu, Guangzhen Cai, Yang Wu, Yunhui Fan, Xiaoping Chen, Hong Zhu, Zeyang Ding, Wanguang Zhang","doi":"10.1002/cac2.70036","DOIUrl":"https://doi.org/10.1002/cac2.70036","url":null,"abstract":"<p><strong>Background: </strong>Intrahepatic cholangiocarcinoma (ICC) is a challenging cancer with an increasing incidence. The Phase III TOPAZ-1/KEYNOTE-966 study demonstrated chemo-immunotherapy (CIT) as a significant advancement, potentially replacing traditional chemotherapy for advanced biliary tract cancer. Ferroptosis is a crucial process that affects cancer cell survival and therapy resistance. Although AKT hyperactivation is prevalent in numerous cancers, including ICC, its role in ferroptosis resistance remains unclear. This study explored whether targeting ferroptosis can enhance CIT response rates, specifically in ICC patients with AKT hyperactivation.</p><p><strong>Methods: </strong>In vivo metabolic CRISPR screening in a Kras^G12D/Tp53^-/- ICC mouse model was used to identify primary regulators of ferroptosis during CIT (gemcitabine, cisplatin, and anti-mouse programmed cell death 1 ligand 1). Phosphoenolpyruvate carboxykinase 1 (PCK1) was assessed for its role in ferroptosis and treatment resistance in preclinical models under AKT activation levels. Molecular and biochemical techniques were used to explore PCK1-related resistance mechanisms in AKT-hyperactivated ICC.</p><p><strong>Results: </strong>Under AKT hyperactivation condition, phosphorylated PCK1 (pPCK1) promoted metabolic reprogramming, enhancing ubiquinol and menaquinone-4 synthesis through the mevalonate (MVA) pathway. This cascade was mediated by the pPCK1-pLDHA-SPRINGlac axis. Inhibiting PCK1 phosphorylation or using simvastatin significantly augmented CIT efficacy in preclinical models. Clinical data further indicated that phosphorylated AKT (pAKT)-pPCK1 levels might serve as a biomarker to predict CIT response in ICC.</p><p><strong>Conclusion: </strong>This study identified the pAKT-pPCK1-pLDHA-SPRINGlac axis as a novel mechanism driving ferroptosis resistance in AKT-hyperactivated ICC by associating glycolytic activation with MVA flux reprogramming. Targeting this axis, potentially through statin-based therapies, may offer a strategy to sensitize ICC cells to ferroptosis and improve treatment outcomes.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180794","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}

{"title":"First-line serplulimab plus chemotherapy in extensive-stage small-cell lung cancer: Updated results and biomarker analysis from the ASTRUM-005 randomized clinical trial.","authors":"Ying Cheng, Shuang Zhang, Liang Han, Lin Wu, Jun Chen, Peiyan Zhao, Hongmei Sun, Guilan Wen, Yinghua Ji, Anastasia Zimina, Jianhua Shi, Zhijie Pan, Jinsheng Shi, Xicheng Wang, Yuansong Bai, Tamar Melkadze, Yueyin Pan, Xuhong Min, Maksym Viguro, Xingya Li, Yanqiu Zhao, Junquan Yang, Tamta Makharadze, Ekaterine Arkania, Haoyu Yu, Jing Li, Fang Yang, Xinyi Yang, Chen Ling, Qingyu Wang, Yongqiang Shan, Jun Zhu","doi":"10.1002/cac2.70032","DOIUrl":"https://doi.org/10.1002/cac2.70032","url":null,"abstract":"<p><strong>Background: </strong>The ASTRUM-005 study previously demonstrated a significant overall survival (OS) benefit with serplulimab (a programmed death 1 inhibitor) plus chemotherapy versus chemotherapy alone in previously untreated extensive-stage small-cell lung cancer (ES-SCLC). Here, we report updated efficacy and safety results after an extended median follow-up of 19.8 months, along with the first report on findings from exploratory biomarker analyses.</p><p><strong>Methods: </strong>A total of 585 patients were randomized in a 2:1 ratio to receive 4.5 mg/kg serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks, together with carboplatin and etoposide. The primary endpoint was OS. In addition, genomic profiling was performed to identify mutated genes, and quantitative serum proteome profiling was conducted to identify differentially expressed proteins (DEPs) between responders and non-responders of serplulimab plus chemotherapy. Regression analysis was subsequently used to construct a protein signature based on the DEPs. The associations between efficacy outcomes (objective response rate [ORR], OS, and progression-free survival [PFS]) and gene mutation status or DEP expression were also examined with regression analysis. Furthermore, the prognostic value of hematological parameters was evaluated.</p><p><strong>Results: </strong>In the intent-to-treat population, the median OS was 15.8 months in the serplulimab group versus 11.1 months in the placebo group (hazard ratio, 0.62; 95% confidence interval, 0.50-0.76; P < 0.001). We identified 181 DEPs between responders and non-responders in the serplulimab group, from which a 15-protein signature was constructed. In the serplulimab group, patients with a higher 15-protein signature score were associated with significantly longer OS and PFS. Also, patients harboring tumor-suppressor retinoblastoma-1 (RB1) mutations or mutations in Notch pathway members showed improved ORR, OS, or PFS compared with their wild-type counterparts. Baseline neutrophil-to-lymphocyte ratio (NLR) and lactate dehydrogenase (LDH) level were independent prognosticators of patients with ES-SCLC.</p><p><strong>Conclusions: </strong>First-line serplulimab provided a sustained clinical benefit over placebo in patients with ES-SCLC. A 15-protein signature and mutations in RB1 or Notch pathway genes may serve as predictive biomarkers for benefits from serplulimab plus chemotherapy, while baseline NLR and LDH were independent prognosticators for ES-SCLC.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov, NCT04063163.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180639","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}

{"title":"Cell-free DNA blood-based test compared to fecal immunochemical test for colorectal cancer screening.","authors":"Teresa Seum, Michael Hoffmeister, Hermann Brenner","doi":"10.1002/cac2.70037","DOIUrl":"https://doi.org/10.1002/cac2.70037","url":null,"abstract":"","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149246","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}

{"title":"A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: durable responses and delayed pseudoprogression in small cell carcinoma of the ovary, hypercalcemic type cohort.","authors":"Young Kwang Chae, Megan Othus, Sandip Pravin Patel, Raid Aljumaily, Khine Z Win, Tanya Pejovic, Sajeve S Thomas, William R Robinson, Hye Sung Kim, Liam Il-Young Chung, Christine M McLeod, Helen X Chen, Elad Sharon, Howard Streicher, Christopher W Ryan, Charles D Blanke, Razelle Kurzrock","doi":"10.1002/cac2.70020","DOIUrl":"https://doi.org/10.1002/cac2.70020","url":null,"abstract":"<p><strong>Background: </strong>The combined use of anti-programmed cell death protein 1 (PD-1)/anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) checkpoint inhibitors has been effective in various cancer types. The Southwest Oncology Group (SWOG) Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) S1609 study investigated ipilimumab and nivolumab in ultra-rare cancers, including small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). The purpose of the study was to evaluate the potential clinical benefit of ipilimumab and nivolumab in patients with SCCOHT.</p><p><strong>Methods: </strong>DART was a prospective, open-labeled, multicenter (>1,000 US sites), multi-cohort phase II clinical trial of intravenous administration of ipilimumab (1 mg/kg, every 6 weeks) plus nivolumab (240 mg, every 2 weeks). The primary endpoint was overall response rate [ORR, confirmed complete response (CR) and partial response (PR)] per RECIST. Secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR; overall response plus stable disease ≥6 months), and toxicity. Immune responses were also evaluated.</p><p><strong>Results: </strong>Six patients (median age, 30.5 years; median, 2 prior therapies; no prior immunotherapy exposure) with advanced/metastatic SCCOHT were evaluable. ORR and CBR were both 16.7% (1/6) with one patient having a confirmed CR lasting 46.2+ months. However, another patient had a confirmed immune CR (iCR) with immune PFS (iPFS) of 53+ months [ORR/iORR, 33.3% (2/6)]. Notably, the latter patient had a progressing lesion at 24 weeks after initial response, but with renewed regression with ongoing therapy, suggesting delayed pseudo-progression. At 12-months, 3 patients remained alive. Median PFS was 1.4 months (range, 0.9 months-not reached); median OS was 14.2 months (2 months-not reached). No adverse events caused treatment discontinuation.</p><p><strong>Conclusion: </strong>Two of 6 patients (33.3%) with SCCOHT achieved durable CR/iCR and long-term survival with ipilimumab plus nivolumab. Correlative studies to determine response and resistance markers are ongoing.</p><p><strong>Clinicaltrials: </strong></p><p><strong>Gov registry: </strong>NCT02834013.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126765","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}

{"title":"Targeted reactivation of the novel tumor suppressor DAPK1, an upstream regulator of p53, in high-grade serous ovarian cancer by mRNA liposomes reduces viability and enhances drug sensitivity in preclinical models.","authors":"Monika Raab, Balázs Győrffy, Samuel Peña-Llopis, Daniela Fietz, Monika Kressin, Margareta Kolaric, Matthias Ebert, Khayal Gasimli, Sven Becker, Mourad Sanhaji, Klaus Strebhardt","doi":"10.1002/cac2.70029","DOIUrl":"https://doi.org/10.1002/cac2.70029","url":null,"abstract":"","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109779","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}

{"title":"Evaluation of exposure-response-safety relationship of model-informed low-dose 500 mg abiraterone acetate in prostate cancer patients.","authors":"Edmund Chiong, Ziteng Wang, Eleanor Jing Yi Cheong, Yi Chen Yao, Sin Mun Tham, Revathi Periaswami, Poh Choo Toh, Ziting Wang, Qing Hui Wu, Woon Chau Tsang, Arshvin Kesavan, Alvin Seng Cheong Wong, Patrick Thomas Wong, Felicia Lim, Shuaibing Liu, Eric Chun Yong Chan","doi":"10.1002/cac2.70035","DOIUrl":"https://doi.org/10.1002/cac2.70035","url":null,"abstract":"","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109777","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}

{"title":"N⁶-methyladenosine-regulated exosome biogenesis orchestrates an immunosuppressive pre-metastatic niche in gastric cancer peritoneal metastasis.","authors":"Song Li, Jianyuan Zhou, Shuang Wang, Qian Yang, Shulun Nie, Chunwang Ji, Xue Zhang, Shuhan Li, Xuanyu Zhou, Jiahui Chu, Xuehui Wu, Jianqiao Jiao, Ruitao Xu, Qian Xu, Miao Huang, Qiushi Wang, Liliang Dou, Qinqin Hu, Fan Jiang, Xin Dai, Zhaodi Nan, Xinyu Song, Di Zhang, Lian Liu","doi":"10.1002/cac2.70034","DOIUrl":"https://doi.org/10.1002/cac2.70034","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer peritoneal metastasis is clinically challenging, given the limited treatment options and poor prognosis. The molecular mechanisms that precede gastric cancer peritoneal metastasis, known as the pre-metastatic niche (PMN), and its relationship with N⁶-methyladenosine (m⁶A) modification remain unclear.</p><p><strong>Methods: </strong>We used 87 resected gastric cancer tissues and 4 public datasets to explore the association between methyltransferase-like 3 (METTL3) expression and gastric cancer peritoneal metastasis. Roles of m⁶A, exosomes, or macrophages in PMN formation were explored in immunocompetent mouse models through exosome treatments or macrophage modifications. Key genes and regulatory mechanisms were uncovered using mass spectrometry, RNA/miRNA sequencing, RNA-immunoprecipitation, dual-luciferase assays, and point mutations in the ras-related protein Rab-27A (RAB27A) in cells. Macrophage and T-cell functions were assessed using enzyme-linked immunosorbent assay, flow cytometry, and cytotoxicity assays.</p><p><strong>Results: </strong>METTL3 overexpression in gastric cancer cells enhanced RAB27A translation by methylating its mRNA A502 base, facilitated by its m⁶A \"reader\" YTH N⁶-methyladenosine RNA binding protein F1 (YTHDF1), and led to increased exosome biogenesis. The miRNA-17-92 cluster was enriched in METTL3-overexpressed cell-derived exosomes and targeted SRC kinase signaling inhibitor 1 (SRCIN1) to activate SRC proto-oncogene, non-receptor tyrosine kinase (SRC) signaling in peritoneal macrophages. Macrophage activation skewed cytokine production towards an immunosuppressive profile in the peritoneum, elevating the levels of interleukin (IL)-10 and tumor necrosis factor (TNF) and reducing the levels of IL-1 and IL-6. These cytokine shifts inhibited T cell proliferation and cytotoxic activities, which created an immunosuppressive PMN and led to peritoneal metastasis. The association between METTL3, macrophages, and peritoneal metastasis was verified in clinical samples.</p><p><strong>Conclusions: </strong>Our study identified an intricate m⁶A-regulated mechanism of peritoneal PMN development that is mediated by exosome-promoted macrophages. These insights into gastric cancer peritoneal metastasis offer promising directions for translational research.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076207","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}