Cancer letters最新文献

{"title":"CUL4A exhibits tumor-suppressing role via regulation of HUWE1-mediated SMAD3 intracellular shuttling.","authors":"Veronika Danek, Jolana Tureckova, Kerstin Huebner, Katharina Erlenbach-Wuensch, Petra Baranova, Jan Dobes, Jana Balounova, Michaela Simova, Vendula Novosadova, Carlos Eduardo Madureira Trufen, Michaela Prochazkova, Pavel Talacko, Karel Harant, Cyril Barinka, Inken M Beck, Regine Schneider-Stock, Radislav Sedlacek, Jan Prochazka","doi":"10.1016/j.canlet.2025.217663","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217663","url":null,"abstract":"<p><p>Changes in cellular physiology and proteomic homeostasis accompanied the initiation and progression of colorectal cancer. Thus, ubiquitination represents a central regulatory mechanism in proteome dynamics. However, the complexity of the ubiquitinating network involved in carcinogenesis remains unclear. This study revealed the tumor-suppressive role of the ubiquitin ligase Cullin4A (CUL4A) in the intestine. We showed that simultaneous loss of CUL4A and hyperactivation of the Wnt pathway promotes tumor development in the distal colon. This tumor development is caused by an accumulation of the inactive SMAD3, a TGF-β pathway mediator. Depletion of CUL4A resulted in stabilization of HUWE1, which attenuated SMAD3 function. We showed a correlation between the intracellular localization of CUL4A and colorectal cancer progression, where nuclear CUL4A localization correlates with advanced colorectal cancer progression. In summary, we identified CUL4A as an important regulator of SMAD3 signal transduction competence in a HUWE1-dependent manner and demonstrated a critical role for the crosstalk between ubiquitination and the Wnt/TGF-β signaling pathways in gastrointestinal homeostasis.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217663"},"PeriodicalIF":9.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691344","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":"Analysis of germline-somatic mutational connections in colorectal cancer reveals differential tumorigenic patterns and a novel predictive marker for germline mutation carriers.","authors":"Mintao Li, Xuan Gao, Xiangchun Lin, Yan Zhang, Wenying Peng, Tao Sun, Weiyang Shu, Yanyan Shi, Yanfang Guan, Xuefeng Xia, Xin Yi, Yuan Li, Jinzhu Jia","doi":"10.1016/j.canlet.2025.217637","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217637","url":null,"abstract":"<p><p>Colorectal cancer (CRC) genetic testing of regions beyond clinical guidelines has revealed a substantial number of likely pathogenic germline mutations (GMs). It remains largely undetermined whether and how these GMs, typically located in non-mismatch repair (non-MMR) genes, are associated with the tumorigenesis of CRC. This study aimed to identify CRC-predisposing GMs among 93 cancer susceptibility genes and investigate their potential influences on CRC somatic mutational features. We secondarily aimed to investigate whether somatic ERBB2 amplification contributes to identifying GM carriers. This study incorporated a total of 3,240 Chinese CRC patients and 10,588 control individuals. CRC patients were subjected to paired tumor-normal sequencing with a 1,021-gene panel. A case-control analysis was conducted to profile the GM-associated CRC risk. A comprehensive germline-somatic association analysis was performed among 2,405 patients, with key findings subsequently validated in an independent 835-patient cohort and the TCGA CRC cohort. The case-control results supported CRC-predisposing effects of GMs in certain homologous recombination repair (HRR) and DNA damage checkpoint factor (CPF) genes, such as BRCA1/2, RecQ helicase genes, ATM, and CHEK2. HRR GMs were associated with an increased copy number alteration burden, more TP53 clonal mutations, and a higher probability of carrying somatic ERBB2 amplification. CPF GMs were inferred to have synergistic effects with ARID1A and KDM6A somatic mutations in CRC tumorigenesis. Among patients with onset age ≥ 55 years, stable microsatellites, and no cancer family history, ERBB2 amplification was significantly predictive of GM carriers. Our findings elucidate different germline tumorigenic patterns not driven by deficient MMR. Somatic ERBB2 amplification in CRC can serve as an indicator for germline genetic testing when traditional risk features are absent.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217637"},"PeriodicalIF":9.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672960","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":"Organoid-based single cell sequencing revealed the lineage evolution during docetaxel treatment in gastric cancer","authors":"Dejun Yang ,&nbsp;Xin Zhang ,&nbsp;Zunqi Hu ,&nbsp;Qiang Sun ,&nbsp;Hongbing Fu ,&nbsp;Jun Yao ,&nbsp;Binbin Zheng ,&nbsp;Xin Zhang ,&nbsp;Weijun Wang","doi":"10.1016/j.canlet.2025.217617","DOIUrl":"10.1016/j.canlet.2025.217617","url":null,"abstract":"<div><div>Docetaxel resistance in gastric cancer poses a major therapeutic challenge. In this study, we established docetaxel-sensitive and -resistant gastric cancer organoids and performed single-cell RNA sequencing to identify cellular and molecular alterations. We observed significant shifts in cell populations, with increased secretory, immune-chemotactic, and transitional gastric cancer cells in the resistant group. Key resistance-related genes, including FOS, IFI27, and PTTG1IP, were upregulated in resistant organoids and gastric cancer patients. A pseudo-time trajectory analysis revealed that resistant cells predominantly occupied terminal differentiation stages. Knocking down FOS, IFI27, and PTTG1IP enhanced docetaxel sensitivity in both cell lines and organoids, regulating ROS production, autophagy, and apoptosis. In vivo, silencing these genes reduced tumor growth in response to docetaxel. These findings suggest that targeting FOS, IFI27, and PTTG1IP could overcome resistance and improve treatment outcomes for gastric cancer patients.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"619 ","pages":"Article 217617"},"PeriodicalIF":9.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672878","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":"5-Year survival rate over 20 % in pancreatic ductal adenocarcinoma: A retrospective study from a Chinese high-volume center","authors":"Xiang Li ,&nbsp;Yiwen Chen ,&nbsp;Guoliang Qiao ,&nbsp;Jian Ni ,&nbsp;Tao Chen ,&nbsp;Yangyang Wang ,&nbsp;Chengyi Wu ,&nbsp;Qi Zhang ,&nbsp;Tao Ma ,&nbsp;Shunliang Gao ,&nbsp;Min Zhang ,&nbsp;Yan Shen ,&nbsp;Jian Wu ,&nbsp;Jun Yu ,&nbsp;Risheng Que ,&nbsp;Xiaochen Zhang ,&nbsp;Ke Sun ,&nbsp;Wenbo Xiao ,&nbsp;Tian'an Jiang ,&nbsp;Xueli Bai ,&nbsp;Tingbo Liang","doi":"10.1016/j.canlet.2025.217658","DOIUrl":"10.1016/j.canlet.2025.217658","url":null,"abstract":"<div><div>Standardized clinical management of pancreatic adenocarcinoma (PDAC) remains challenging and high-volume centers provide essential insights for establishing effective multimodal treatment approaches. This retrospective observational study evaluated the impact of standardized, multimodal clinical management on survival outcomes in patients with PDAC across all stages, based on NCCN guidelines resectability criteria, at a high-volume center<strong>.</strong> From 2019, 4143 patients were diagnosed with PDAC, with 3268 patients receiving further treatment, including surgical resection and/or systemic therapy. The median overall survival (OS) was 18.5 (95 %CI 17.5–19.4) months for the treated cohort and the 5-year survival rate reached 23.3 %. Patients who underwent surgical resection had significantly improved median OS compared to those who received non-surgical treatments (28.4 months vs. 13.0 months, <em>P</em> &lt; 0.001), with corresponding 5-year survival rates of 31.6 % vs. 15.0 %. Moreover, the patients who received NAT followed by surgical resection had improved survival outcomes compared to those who underwent upfront surgical resection in both resectable (median OS: 37.5 months vs. 28.9 months, P &lt; 0.01) and borderline resectable group (median OS: 31.8 months vs. 18.4 months, P &lt; 0.001). This study demonstrated a 5-year survival rate exceeding 20 % for PDAC across all stages at our center. The application of evidence-based treatment strategies through the multidisciplinary team, accompanying with standardized and comprehensive therapeutic managements, high patient adherence, have been considered as critical determinants in enhancing therapeutic efficacy and improving long-term prognosis for patients with PDAC.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"619 ","pages":"Article 217658"},"PeriodicalIF":9.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673389","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":"Unraveling the molecular mechanism underlying the anticancer activity of CISD2/NAF-144−67","authors":"Linda Rowland ,&nbsp;Itai Alfoni ,&nbsp;Ehud Neumann ,&nbsp;Ola Karmi ,&nbsp;Rachel Nechushtai ,&nbsp;Ron Mittler","doi":"10.1016/j.canlet.2025.217644","DOIUrl":"10.1016/j.canlet.2025.217644","url":null,"abstract":"<div><div>We recently reported on the development of a unique cancer-targeting peptide called NAF-1⁴⁴⁻⁶⁷ (derived from CISD2/NAF-1). NAF-1⁴⁴⁻⁶⁷ selectively permeates the plasma membrane (PM) of cancer cells, but not healthy cells, causing the activation of apoptotic and ferroptotic cell death pathways specifically in cancer cells. NAF-1⁴⁴⁻⁶⁷ also targets and shrinks human breast and ovarian cancer tumors in a xenograft mice model system without any apparent side effects. Although the specific permeation of NAF-1⁴⁴⁻⁶⁷ through cancer cell PMs was studied, and its cancer killing effects validated <em>in vitro</em> and <em>in vivo</em>, little is known about how NAF-1⁴⁴⁻⁶⁷ exerts its biological activity once it enters cancer cells. Here, we report that NAF-1⁴⁴⁻⁶⁷ targets the CISD2/NAF-1 protein of cancer cells and disrupts its homodimeric structure. We further reveal that a peptide derived from the same domain of the human CISD1 (mitoNEET; mNT^19-42) protein, a close family member to CISD2, has no killing activity towards cancer cells, and that dimers of NAF-1⁴⁴⁻⁶⁷ (at two different orientations) have higher anticancer activity compared to monomeric NAF-1⁴⁴⁻⁶⁷. Our findings shed new light on the biological activity of NAF-1⁴⁴⁻⁶⁷ and bring it closer to becoming a potential new anticancer drug.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"619 ","pages":"Article 217644"},"PeriodicalIF":9.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143672896","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":"FUT2-dependent fucosylation of LAMP1 promotes the apoptosis of colorectal cancer cells by regulating the autophagy-lysosomal pathway","authors":"Zijun Guo ,&nbsp;Lingnan He ,&nbsp;Weijun Wang ,&nbsp;Shuxin Tian ,&nbsp;Rong Lin","doi":"10.1016/j.canlet.2025.217643","DOIUrl":"10.1016/j.canlet.2025.217643","url":null,"abstract":"<div><div>Fucosyltransferase 2 (FUT2) is an enzyme that adds fucose to proteins or lipids via α-1,2-fucosylation in the intestinal mucosa. While FUT2 deficiency is linked to increased susceptibility to inflammatory bowel disease (IBD), its role in colorectal cancer (CRC) is unclear, and the molecular mechanisms involved remain largely unknown. We established an azoxymethane (AOM) and dextran sulfate sodium (DSS) model to induce CRC. FUT2 expression was assessed in human CRC tissues, AOM/DSS-induced mouse models, and CRC cell lines using qRT-PCR, western blotting, and UEA-I staining. FUT2 knockout (FUT2^△IEC) mice were treated with AOM/DSS, and FUT2-overexpressing CRC cells were created to evaluate the effects of FUT2 on apoptosis in both <em>in vitro</em> and <em>in vivo</em> settings through Western blot analyses and functional assays. N-glycoproteomics, UEA-I chromatography, and co-immunoprecipitation were utilized to identify regulatory mechanisms and target fucosylated proteins. FUT2 expression and α-1,2-fucosylation were significantly decreased in CRC. FUT2 deficiency worsened AOM/DSS-induced CRC and reduced tumor apoptosis, while FUT2 overexpression induced apoptosis and inhibited proliferation in CRC cells and xenografts. Mechanistically, FUT2 appears to suppress autophagy by impairing lysosomal function and directly targeting and fucosylating LAMP1, contributing to lysosomal dysfunction. Our study reveals a fucosylation-dependent antitumor mechanism of FUT2 in CRC, suggesting potential therapeutic strategies for CRC treatment.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"619 ","pages":"Article 217643"},"PeriodicalIF":9.1,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669210","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":"GENERATING RESEARCH HYPOTHESES TO OVERCOME KEY CHALLENGES IN THE EARLY DIAGNOSIS OF COLORECTAL CANCER - FUTURE APPLICATION OF AI.","authors":"Lan Yao, Heliang Yin, Chengyuan Yang, Shuyan Han, Jiamin Ma, J Carolyn Graff, Cong-Yi Wang, Yan Jiao, Jiafu Ji, Weikuan Gu, Gang Wang","doi":"10.1016/j.canlet.2025.217632","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217632","url":null,"abstract":"<p><p>We intend to explore the capability of ChatGPT 4.0 in generating innovative research hypotheses to address key challenges in the early diagnosis of colorectal cancer (CRC). We asked ChatGPT to generate hypotheses focusing on three main challenges: improving screening accuracy, overcoming technological limitations, and identifying reliable biomarkers. The hypotheses were evaluated for novelty. The experimental plans provided by ChatGPT for selected hypotheses were assessed for completion and feasibility. As a result, ChatGPT generated a total of 65 hypotheses. ChatGPT rated all 65 hypotheses, with 25 hypotheses receiving the highest rating (5) and 40 hypotheses receiving a rating of 4 or lower. The research team evaluated a total of 65 hypotheses, assigning them the following grades: hypotheses were rated as excellent (Grade 5), 16 were deemed suitable (Grade 4), 31 were classified as satisfactory (Grade 3), 12 were identified as needing Improvement (Grade 2), and one was considered poor (Grade 1). Additionally, the study determined that 17 of the generated hypotheses had corresponding publications. Out of the three experimental plans assessed, one was rated excellent (5) for feasibility, while the others received good (4) and moderate (3) ratings. Predicted outcomes and alternative approaches were rated as good, with some areas requiring further improvement. Our data demonstrate that AI has the potential to revolutionize hypothesis generation in medical research, though further validation through experimental and clinical studies is needed. This study suggests that while AI can generate novel hypotheses, human expertise is essential for evaluating their practicality and relevance in scientific research.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217632"},"PeriodicalIF":9.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646898","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":"Fibrinogen-like 2 in tumor-associated macrophage-derived extracellular vesicles shapes an immunosuppressive microenvironment in colorectal liver metastases by promoting tumor stemness and neutrophil extracellular traps formation","authors":"Menghua Zhou ,&nbsp;Bingjie Guan ,&nbsp;Youdong Liu ,&nbsp;Qi Gu ,&nbsp;Weiwei Chen ,&nbsp;Bowen Xie ,&nbsp;Mantang Zhou ,&nbsp;Jianjun Xiang ,&nbsp;Senlin Zhao ,&nbsp;Qian Zhao ,&nbsp;Dongwang Yan","doi":"10.1016/j.canlet.2025.217642","DOIUrl":"10.1016/j.canlet.2025.217642","url":null,"abstract":"<div><div>Investigating the mechanisms underlying the development of an immunosuppressive microenvironment within colorectal liver metastases (CRLM) is important for identifying synergistic targets for immunotherapy. The regulatory role of tumor-associated macrophage-derived extracellular vesicles (TAM-EVs) in the immune microenvironment of CRLM has not yet been fully explored. Here, we found that TAM-EVs shaped the immunosuppressive microenvironment at the invasive front in murine CRLM models, thus dampening anti-PD-1 immunotherapy. This environment is characterized by an increased tumor stemness potential and abundant neutrophil extracellular traps (NETs) formation. Mechanistically, TAM-EVs-derived fibrinogen-like 2 (FGL2) interacts with the FCGR2B receptor in tumor cells, which further activates a p-STAT3/IL-1β positive feedback loop to increase the stemness potential of cancer cells, whereas IL-1β mediates the communication between cancer cells and neutrophils. The use of an anti-IL-1β monoclonal antibody can reduce NETs production and synergize with anti-PD-1 immunotherapy, which offers clinical translational significance for CRLM therapy. The FGL2/p-STAT3/IL-1β loop correlates with an immunosuppressive microenvironment and poor prognosis in human patients with CRLM. Our results revealed the potential of enhancing the efficacy of immunotherapy via the targeted clearance of NETs using anti-IL-1β monoclonal antibodies, which have significant clinical translational value in the treatment of CRLM.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"618 ","pages":"Article 217642"},"PeriodicalIF":9.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143644754","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":"CircRUNX1 enhances the Warburg effect and immune evasion in non-small cell lung cancer through the miR-145/HK2 pathway.","authors":"Jinyou Li, Shiwei Xu, Yangyang Zhan, Xinyi Lv, Zhenyu Sun, Li Man, Donghua Yang, Yahong Sun, Shengguang Ding","doi":"10.1016/j.canlet.2025.217639","DOIUrl":"https://doi.org/10.1016/j.canlet.2025.217639","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) is acknowledged as the primary subtype of lung cancer. The Warburg effect, marked by elevated glucose consumption and lactate fermentation, is a prevalent characteristic of NSCLC. The mechanisms by which circRNA mediates the regulation of the Warburg effect and immune evasion in NSCLC remain unclear.. This study found an elevated circRNA, circRUNX1, whiche promotes glycolysis and lactate generation, resulting in the infiltration of regulatory T cell (Treg) in NSCLC. circRUNX1 acts as a miR-145 sponge, inhibiting its negative regulation of the target gene HK2, therefore facilitating glycolysis and lactate generation. The accumulation of lactic acid in the tumor microenvironment promotes Treg cell proliferation and aids immune evasion. Functionally, the suppression of circRUNX1 significantly impedes tumor development both in vitro and in vivo. These findings collectively clarity a previously unexamined mechanism linking the circRUNX1/miR-145/HK2 axis in regulation of the Warburg effect and immune evasion in NSCLC.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217639"},"PeriodicalIF":9.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639525","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":"Spatial distribution and activation changes of T cells in pancreatic tumors according to KRAS mutation subtype","authors":"Ji Hye Jeong ,&nbsp;Dakyum Shin ,&nbsp;Sang-Yeob Kim ,&nbsp;Dong-Jun Bae ,&nbsp;Young Hoon Sung ,&nbsp;Eun-Young Koh ,&nbsp;Jinju Kim ,&nbsp;Chong Jai Kim ,&nbsp;Jae Soon Park ,&nbsp;Jung Kyoon Choi ,&nbsp;Song Cheol Kim ,&nbsp;Eunsung Jun","doi":"10.1016/j.canlet.2025.217641","DOIUrl":"10.1016/j.canlet.2025.217641","url":null,"abstract":"<div><div>To enhance immunotherapy efficacy in pancreatic cancer, it is crucial to characterize its immune landscape and identify key factors driving immune alterations. To achieve this, we quantitatively analyzed the immune microenvironment using multiplex immunohistochemistry, assessing the spatial relationships between immune and tumor cells to correlate with patient survival rates and oncological factors. Additionally, through Whole Exome Sequencing analysis based on public data, we explored genetic mutations that could drive these compositions. Finally, we validated T cell (Tc) migration mechanisms using patient-derived tumor organoids with induced KRAS mutation subtypes. Through this approach, we obtained the following meaningful results<strong>.</strong> First, immune cells in pancreatic cancer are denser in stromal regions than near tumor cells, with higher Tc distribution linked to increased patient survival rates. Second, the distance between tumor and Tc was within 100 μm, with higher Tc density found within 15–30 μm of the tumor cells. Third, while increasing CAF levels correspond to higher Tc density, higher ECM density tends to decrease Tc presence. Fourth, compared to KRAS G12D, KRAS G12V mutation increases various immune cells, notably Tc, which is closely linked to a dramatic rise in vascular cells. Finally, Tc migration was enhanced in tumor organoids with the G12V mutation, attributed to a reduction in the secretion of immunosuppressive cytokines. Our results indicate that KRAS mutation subtypes influence immune cell composition and function in the pancreatic cancer microenvironment, leading to varied immunotherapy responses. This underscores the need for personalized immune therapeutics and research models specific to KRAS mutations.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"618 ","pages":"Article 217641"},"PeriodicalIF":9.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639462","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}