Cancer Science最新文献

Permeable Lung Vasculature Creates Chemoresistant Endothelial Niche by Producing SERPINE1 at Breast Cancer Metastatic Sites 可渗透的肺血管通过在乳腺癌转移部位产生SERPINE1产生化疗耐药内皮生态位。

IF 4.5 2区医学

Cancer Science Pub Date : 2025-04-11 DOI: 10.1111/cas.70050

Tsunaki Hongu, Sarenqiqige, Shandan, Hirokazu Kusunoki, Akihiko Ishimura, Takeshi Suzuki, Thordur Oskarsson, Noriko Gotoh

{"title":"Permeable Lung Vasculature Creates Chemoresistant Endothelial Niche by Producing SERPINE1 at Breast Cancer Metastatic Sites","authors":"Tsunaki Hongu,  Sarenqiqige,  Shandan, Hirokazu Kusunoki, Akihiko Ishimura, Takeshi Suzuki, Thordur Oskarsson, Noriko Gotoh","doi":"10.1111/cas.70050","DOIUrl":"10.1111/cas.70050","url":null,"abstract":"Chemotherapy resistance remains a major obstacle for eradicating metastatic cancer cells in distant organs. We identified that endothelial cells (ECs) in the lungs, where breast cancer cells often metastasize, form a chemoresistant perivascular niche for disseminated breast cancer cells. By investigating the lung EC secretome activated by metastasis, we found that serine protease inhibitor family E member 1 (SERPINE1), encoded by Serpine1, is upregulated in metastasis-associated lung ECs. This upregulation shields cancer cells from paclitaxel-induced apoptosis and promotes cancer stem cell properties. Serpine1 expression appears to be driven by YAP-TEAD activation in lung ECs that lose cell–cell contact, a phenomenon associated with increased vascular permeability in lungs affected by metastasis. Crucially, pharmacological inhibition of SERPINE1 enhances the chemotherapy sensitivity of metastatic breast cancer cells in the lung. Overall, our findings underscore the pivotal role of the vascular niche, which produces SERPINE1, in conferring chemoresistance to breast cancer cells during metastatic progression in the lungs.","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1604-1615"},"PeriodicalIF":4.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70050","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pimitespib, an HSP90 Inhibitor, Enhances the Efficacy of PARP Inhibitors in PARP Inhibitor-Insensitive Breast Cancer Cells HSP90抑制剂piitespib增强PARP抑制剂对PARP抑制剂不敏感的乳腺癌细胞的疗效

IF 4.5 2区医学

Cancer Science Pub Date : 2025-04-01 DOI: 10.1111/cas.70058

Hiromi Muraoka, Hiromi Kazuno, Akihiro Hashimoto, Hiroshi Sootome, Shuichi Ohkubo

{"title":"Pimitespib, an HSP90 Inhibitor, Enhances the Efficacy of PARP Inhibitors in PARP Inhibitor-Insensitive Breast Cancer Cells","authors":"Hiromi Muraoka, Hiromi Kazuno, Akihiro Hashimoto, Hiroshi Sootome, Shuichi Ohkubo","doi":"10.1111/cas.70058","DOIUrl":"10.1111/cas.70058","url":null,"abstract":"Heat shock protein 90 (HSP90) plays a crucial role in the maintenance of protein homeostasis in cancer cells. Inhibition of HSP90 is anticipated to exert anticancer activities by reducing levels of HSP90 client proteins. Pimitespib (TAS-116) has emerged as a potent ATP-competitive inhibitor of both HSP90α and β, demonstrating favorable therapeutic properties in preclinical models. Notably, pimitespib is the first HSP90 inhibitor approved for the treatment of advanced gastrointestinal stromal tumors in Japan. Poly(ADP-ribose) polymerase (PARP) inhibitors target cancers susceptible to the homologous recombination (HR) pathway and are used for treating various types of tumors, particularly those harboring defects in HR repair pathways within DNA damage repair (DDR) such as mutations in breast cancer genes 1 and 2 (BRCA1 and BRCA2, respectively). However, PARP inhibitors have shown limited efficacy in HR-proficient tumors, and the development of resistance to PARP inhibitors via restoration of DDR systems poses a significant challenge. In this study, we explored the potential of pimitespib to enhance PARP inhibitor activity. In PARP inhibitor-insensitive breast cancer cell lines, pimitespib impaired HR pathway function by promoting the proteasome-mediated degradation of proteins involved in HR, such as BRCA1, BRCA2, and Rad51 homologous 1 (RAD51). Consequently, pimitespib enhanced antitumor activity and DNA damage induced by PARP inhibitors in vitro. In human breast cancer xenograft mouse models, pimitespib downregulated RAD51 proteins and augmented the antitumor effects of PARP inhibitors. These findings highlight the potential of pimitespib as a therapeutic agent in combination with PARP inhibitors to treat PARP inhibitor-insensitive cancers.","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1745-1757"},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70058","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143755376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction to “Loss of Polarity Protein Par3, via Transcription Factor Snail, Promotes Bladder Cancer Metastasis” 更正“极性蛋白Par3的缺失，通过转录因子蜗牛，促进膀胱癌转移”。

IF 4.5 2区医学

Cancer Science Pub Date : 2025-04-01 DOI: 10.1111/cas.70073

引用次数: 0

Correction to “Celastrol Induces Proteasomal Degradation of FANCD2 to Sensitize Lung Cancer Cells to DNA Crosslinking Agents” 更正“Celastrol诱导蛋白酶体降解FANCD2使肺癌细胞对DNA交联剂敏感”。

IF 4.5 2区医学

Cancer Science Pub Date : 2025-03-29 DOI: 10.1111/cas.70066

引用次数: 0

A Multicenter Phase II Trial of Nimustine Hydrochloride Administered via Convection-Enhanced Delivery in Children With DIPG 一项多中心II期临床试验盐酸尼莫司汀通过对流增强分娩治疗DIPG患儿。

IF 4.5 2区医学

Cancer Science Pub Date : 2025-03-27 DOI: 10.1111/cas.70054

Ryuta Saito, Masayuki Kanamori, Yoshiki Arakawa, Yohei Mineharu, Yasuo Aihara, Kentaro Chiba, Toshihiro Kumabe, Ichiyo Shibahara, Yukihiko Sonoda, Kenichiro Matsuda, Manabu Kinoshita, Aya Sato, Fumiaki Takahashi, Teiji Tominaga

{"title":"A Multicenter Phase II Trial of Nimustine Hydrochloride Administered via Convection-Enhanced Delivery in Children With DIPG","authors":"Ryuta Saito, Masayuki Kanamori, Yoshiki Arakawa, Yohei Mineharu, Yasuo Aihara, Kentaro Chiba, Toshihiro Kumabe, Ichiyo Shibahara, Yukihiko Sonoda, Kenichiro Matsuda, Manabu Kinoshita, Aya Sato, Fumiaki Takahashi, Teiji Tominaga","doi":"10.1111/cas.70054","DOIUrl":"10.1111/cas.70054","url":null,"abstract":"Diffuse intrinsic pontine glioma (DIPG) is a very challenging-to-treat pediatric malignant tumor, with a median survival time of < 12 months. Convection-enhanced delivery (CED) allows for direct drug administration into the tumor site, showing potential as a novel therapeutic approach. This study evaluated the efficacy of CED of nimustine hydrochloride (ACNU) in children with DIPG. This phase 2, single-arm, multicenter study enrolled patients aged 3–21 years and diagnosed with DIPG. The investigational treatment commenced 1 month after completing radiotherapy (local 50–60 Gy). The treatment involved stereotactic brain surgery for catheter placement, followed by ACNU administration via a CED catheter at a concentration of 0.75 mg/mL for 2–3 days until a cumulative dose of 7 (±0.3) mL was achieved. The primary endpoint was the 1-year survival rate. From April 2018 to March 2020, 21 children were enrolled in the trial and treated, with 20 evaluable for the primary endpoint. The 1-year survival rate from the start of radiotherapy was 60%, and the median survival time was 15 months. The response rate was analyzed in 20 patients, with one complete response (CR), six partial responses (PR), nine stable diseases, and four progressive diseases, resulting in a response rate of 35% (CR + PR). The CED of ACNU in the brainstem of children with DIPG after radiotherapy appears to be an effective therapeutic strategy. This approach warrants further development as a treatment for children with DIPG. This study is registered with jRCT (No. jRCT2021190003).","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1679-1690"},"PeriodicalIF":4.5,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143732685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Targeting Cancer With Bifunctional Peptides: Mechanism of Cell Entry and Inciting Cell Death 双功能肽靶向肿瘤：细胞进入和刺激细胞死亡的机制。

IF 4.5 2区医学

Cancer Science Pub Date : 2025-03-26 DOI: 10.1111/cas.70065

Maria F. Setiawan, Oliver Rudan, Ingo G. H. Schmidt-Wolf

{"title":"Targeting Cancer With Bifunctional Peptides: Mechanism of Cell Entry and Inciting Cell Death","authors":"Maria F. Setiawan, Oliver Rudan, Ingo G. H. Schmidt-Wolf","doi":"10.1111/cas.70065","DOIUrl":"10.1111/cas.70065","url":null,"abstract":"Antimicrobial peptides have gained much attention in clinical research due to their extensive possibilities of application beyond antimicrobial use. The modification of antimicrobial peptides enables the peptides to target particular cancer cells, improving the specificity and efficiency of the treatment. In this study, TP2-D-Tox, a derivative of TP-D-Tox, demonstrated a superior anti-tumor activity towards renal carcinoma, Caki-2, and breast carcinoma, SK-BR-3. TP-Tox was previously reported to inhibit tumor growth in a mouse model, increasing the overall survival. TP- and TP2-D-Tox were shown to penetrate the cells via clathrin-mediated endocytosis, triggered by binding to the subunits of non-muscle myosin IIa and S100A9. HSPB1 was observed to have a protective effect towards TP2-D-Tox against the immediate proteolytic inactivation. The intracellular presence of the peptides evoked mitochondrial permeability transition, generation of reactive oxygen species, and formation of MLKL oligomers in the plasma membrane. Our investigation revealed that TP- and TP2-D-Tox induced a similar but distinctly regulated cell death in Caki-2 and SK-BR-3 cells. Both peptides established toxicity without activating any caspases, suggesting the possibility of TP- and TP2-D-Tox as a promising approach to bypass the caspase-dependent apoptosis-resistance issue impairing therapeutic responses of many cancer treatments.","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1730-1744"},"PeriodicalIF":4.5,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70065","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143732688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Differentiation of Cytotoxic CD8+ T Cell Subsets Under Tumor Progression: Can CD69 Be a New Therapeutic Target? 肿瘤进展中细胞毒性CD8+ T细胞亚群的分化：CD69能成为新的治疗靶点吗？

IF 4.5 2区医学

Cancer Science Pub Date : 2025-03-25 DOI: 10.1111/cas.70055

Ryo Koyama-Nasu, Yangsong Wang, Hinata Miyano, Motoko Y. Kimura

{"title":"Differentiation of Cytotoxic CD8+ T Cell Subsets Under Tumor Progression: Can CD69 Be a New Therapeutic Target?","authors":"Ryo Koyama-Nasu, Yangsong Wang, Hinata Miyano, Motoko Y. Kimura","doi":"10.1111/cas.70055","DOIUrl":"10.1111/cas.70055","url":null,"abstract":"Tumor-specific CD8+ T cells play a pivotal role in anti-tumor immunity. Here, we review the heterogeneity of CD8+ T cell subsets during tumor progression. While both acute and chronic viral infections induce distinct CD8+ T cell responses, chronic responses are also observed during tumor development. Chronic immune responses have traditionally been considered to represent a dysfunctional state of CD8+ T cells, whereas the identification of TCF1+ stem-like CD8+ T cells has highlighted their importance in anti-tumor immunity. During tumor progression, TCF1+ stem-like CD8+ T cells differentiate into cytotoxic Tim-3+ terminally differentiated CD8+ T cells through mechanisms that remain largely unknown. We recently identified CD69 as an important regulator of chronic CD8+ T cell responses and showed that blocking CD69 function, either through the administration of anti-CD69 antibody (Ab) or genetic knockout, enhanced the generation of cytotoxic Tim-3+ terminally differentiated CD8+ T cells in both tumor-draining lymph nodes (TDLNs) and the tumor microenvironment (TME), thereby enhancing the anti-tumor immune response. These findings suggest that CD69 is an attractive therapeutic target that controls the chronic anti-tumor CD8+ T cell response.","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1500-1507"},"PeriodicalIF":4.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70055","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CNDP1 Overexpression by Promoter Hypomethylation Predicts Poor Prognosis and Immunotherapy Response in Mucosal Melanoma 启动子低甲基化介导的CNDP1过表达预测粘膜黑色素瘤的不良预后和免疫治疗反应。

IF 4.5 2区医学

Cancer Science Pub Date : 2025-03-25 DOI: 10.1111/cas.70062

Jia Jia, Junjie Gu, Lina Gao, Kaihua Liu, Jie Dai, Fanshuang Zhang, Pei Yuan, Lili Mao, Xiaoting Wei, Yang Shao, Jun Guo, Yanfeng Xi, Jianming Ying, Lu Si

{"title":"CNDP1 Overexpression by Promoter Hypomethylation Predicts Poor Prognosis and Immunotherapy Response in Mucosal Melanoma","authors":"Jia Jia, Junjie Gu, Lina Gao, Kaihua Liu, Jie Dai, Fanshuang Zhang, Pei Yuan, Lili Mao, Xiaoting Wei, Yang Shao, Jun Guo, Yanfeng Xi, Jianming Ying, Lu Si","doi":"10.1111/cas.70062","DOIUrl":"10.1111/cas.70062","url":null,"abstract":"Mucosal melanoma (MM) is an uncommon and aggressive malignant tumor, characterized by a scarcity of effective treatment options and novel biomarkers. To develop novel biomarkers, a total of 89 MM tumor samples (including 50 cases in the discovery cohort and 39 cases in the validation cohort) were collected from three medical centers. Targeted bisulfite sequencing and RNA sequencing were conducted in the discovery cohort, and Cox regression analysis was employed to evaluate DNA methylation (methyDNA) and RNA expression data. Our results revealed that, compared to control samples, MM tumor samples exhibited a hypomethylated status of the Carnosine dipeptidase 1 (CNDP1) promoter (p < 0.001), which significantly up-regulated its gene expression (R = −0.815, p < 0.001) and indicated a worse prognosis (p = 0.002, hazard ratio (HR) (95% confidence interval, CI) = 0.01 (6.78E-04 ~ 0.20)). Using immunohistochemical staining, we found that CNDP1 protein was expressed in 81.8% of MM cases (36/44, including 1+/2+/3+), and high expression (2+/3+) was associated with significantly decreased overall survival (p = 0.0120, HR (95% CI) = 2.693 (1.223–5.931)). This pattern is consistent across both discovery and validation cohorts. Moreover, among the 21 patients who received immunotherapy, those with hypomethylated CNDP1 were associated with a ‘cold’ tumor immune microenvironment and suboptimal therapeutic outcomes (Objective Response Rate: 38% vs. 60%; Disease Control Rate: 75% vs. 100%). In conclusion, the overexpression of CNDP1, driven by promoter hypomethylation, may serve as a potential predictor of poor prognosis and diminished response to immunotherapy in MM.","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1671-1678"},"PeriodicalIF":4.5,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143711824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Detection of KRAS Mutations Using Extracellular Vesicle DNA in Colorectal Cancer Patients 利用细胞外囊泡DNA检测结直肠癌患者KRAS突变。

IF 4.5 2区医学

Cancer Science Pub Date : 2025-03-24 DOI: 10.1111/cas.70059

Sho Kuriyama, Takeshi Yamada, Toshimitsu Miyasaka, Kay Uehara, Ryo Ohta, Akihisa Matsuda, Goro Takahashi, Takuma Iwai, Kohki Takeda, Koji Ueda, Shintaro Kanaka, Yasuyuki Yokoyama, Seiichi Shinji, Hiromichi Sonoda, Takeshi Nagasaka, Hiroshi Yoshida

{"title":"Detection of KRAS Mutations Using Extracellular Vesicle DNA in Colorectal Cancer Patients","authors":"Sho Kuriyama, Takeshi Yamada, Toshimitsu Miyasaka, Kay Uehara, Ryo Ohta, Akihisa Matsuda, Goro Takahashi, Takuma Iwai, Kohki Takeda, Koji Ueda, Shintaro Kanaka, Yasuyuki Yokoyama, Seiichi Shinji, Hiromichi Sonoda, Takeshi Nagasaka, Hiroshi Yoshida","doi":"10.1111/cas.70059","DOIUrl":"10.1111/cas.70059","url":null,"abstract":"Liquid biopsy using circulating tumor DNA (ctDNA) is useful for precision medicine and molecular-guided oncology; however, its sensitivity is insufficient. We focused on DNA in extracellular vesicles (evDNA) as a new target for liquid biopsy and investigated its sensitivity. This observational study included 334 Stage I–IV colorectal cancer patients. evDNAs and ctDNAs were extracted from plasma collected before surgery. KRAS mutation status was analyzed using droplet digital PCR. One hundred and forty-eight patients had KRAS mutations in tumor tissues, and 186 patients had no KRAS mutations. In Stage II (Stage II 37.8% vs. 13.3%, p = 0.015) or III (Stage III 43.1% vs. 13.6%, p = 0.001) patients, sensitivities to detect KRAS mutations using evDNA were higher than those using ctDNA. Surprisingly, evDNA identified KRAS mutations in 13.8% of patients who lacked them in tumor tissue samples. Among Stage III patients, those with higher concentrations of evDNA had significantly poorer relapse-free survival compared with those who had lower concentrations of evDNA (p = 0.043). The use of evDNA improved the identification rate of KRAS mutations. By using evDNA, KRAS mutations were identified in more than 10% of patients without KRAS mutations in their tumor tissues. The concentration of evDNA can be a prognostic factor for Stage III colorectal cancer patients.","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1661-1670"},"PeriodicalIF":4.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exosomal PKM2: A Noninvasive Diagnostic Marker Linking Macrophage Metabolic Reprogramming to Gastric Cancer Pathogenesis 外泌体PKM2：巨噬细胞代谢重编程与胃癌发病机制的无创诊断标志物

IF 4.5 2区医学

Cancer Science Pub Date : 2025-03-24 DOI: 10.1111/cas.70056

Mengyun Yuan, Xiaoxia Zheng, Shanshan Zheng, Huaizhi Li, Xingxing Zhang, Yuxuan Chen, Xiang Zhang, Bo Han, Wei Wei, Jian Wu, Qingmin Sun

{"title":"Exosomal PKM2: A Noninvasive Diagnostic Marker Linking Macrophage Metabolic Reprogramming to Gastric Cancer Pathogenesis","authors":"Mengyun Yuan, Xiaoxia Zheng, Shanshan Zheng, Huaizhi Li, Xingxing Zhang, Yuxuan Chen, Xiang Zhang, Bo Han, Wei Wei, Jian Wu, Qingmin Sun","doi":"10.1111/cas.70056","DOIUrl":"10.1111/cas.70056","url":null,"abstract":"Tumor-derived exosomes (TDEs) have emerged as vital biomarkers of multiple cancers. However, the diagnostic and stage-predicting effects of exosomal pyruvate kinase isoenzyme type M2 (PKM2) in peripheral blood and its mechanism in promoting gastric cancer (GC) remain unclear. Here, we analyzed plasma exosomal PKM2 in 216 blood samples collected from GC patients and healthy donors (HD). The area under the curve (AUC) of plasma exosomal PKM2 demonstrated superior performance in early GC diagnosis compared with that of widely used clinical biomarkers. Kaplan–Meier analysis revealed that high exosomal PKM2 expression was associated with poor prognosis in patients with GC (HR = 1.623, p = 0.029). Single-cell transcriptome sequencing analysis showed that PKM2 was enriched in tumor-associated macrophages (TAM). We further confirmed that the polarization of TAM to the pro-tumoral M2 phenotype induced by exosomal PKM2 promoted the proliferation, migration, and invasion of GC cells. Mechanistically, exosomal PKM2 enhanced lipid synthesis in TAM by inhibiting SCAP polyubiquitination, which triggered the nuclear accumulation of SREBP1, thereby upregulating fatty acid synthesis enzymes, such as FASN, ACACA, and ACLY. In conclusion, plasma exosomal PKM2 is a promising novel biomarker for the clinical diagnosis of GC. Importantly, exosomal PKM2 shapes the tumor microenvironment by activating the SREBP1-related lipid synthesis pathway in macrophages, thereby contributing to GC development.","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1537-1549"},"PeriodicalIF":4.5,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0