Although perioperative immunotherapy combined with neoadjuvant chemotherapy has improved the clinical outcomes of patients with resectable non-small cell lung cancer (NSCLC), the optimal combination strategy remains unknown. This multicenter, open-label, randomized, phase II trial (ALTER-L043; NCT04846634) evaluated the efficacy and safety of perioperative penpulimab plus anlotinib with or without neoadjuvant chemotherapy in patients with resectable NSCLC. Eligible patients were randomly assigned (1:1:1) to receive 3-4 cycles of neoadjuvant penpulimab (200 mg on day 1) plus anlotinib (12 mg on days 1-14) and chemotherapy, penpulimab plus chemotherapy, or penpulimab plus anlotinib, followed by surgery and matching adjuvant therapy. The primary endpoint was the investigator-assessed major pathologic response (MPR) rate. Between December 3, 2021, and January 23, 2024, 90 patients were randomly assigned to the penpulimab plus anlotinib and chemotherapy (n = 30), penpulimab plus chemotherapy (n = 30), or penpulimab plus anlotinib (n = 30) groups. Definitive surgery was performed in 92.6%, 89.7%, and 70.0% of patients, respectively. Among those who underwent surgery, the MPR and pathological complete response rates were 76.0% (95% CI 54.9-90.6) and 52.0% (95% CI 31.3-72.2), respectively, in the penpulimab plus anlotinib and chemotherapy group; 57.7% (95% CI 36.9-76.7) and 50.0% (95% CI 29.9-70.1), respectively, in the penpulimab plus chemotherapy group; and 52.4% (95% CI 29.8-74.3) and 38.1% (95% CI 18.1-61.6), respectively, in the penpulimab plus anlotinib group. Across all treatment phases, the incidences of grade ≥3 treatment-related adverse events were 26.7%, 20.0%, and 30.0%, respectively. Penpulimab plus anlotinib with or without neoadjuvant chemotherapy demonstrated promising efficacy and a manageable safety profile in patients with resectable NSCLC, suggesting its potential as a viable perioperative treatment option.
尽管围手术期免疫治疗联合新辅助化疗改善了可切除非小细胞肺癌（NSCLC）患者的临床预后，但最佳联合策略仍不清楚。这项多中心、开放标签、随机、II期试验（alt - l043; NCT04846634）评估了可切除的非小细胞肺癌患者围手术期penpulimab + anlotinib联合或不联合新辅助化疗的有效性和安全性。符合条件的患者被随机分配（1:1:1）接受3-4个周期的新辅助彭普利单抗（第1天200 mg） +安洛替尼（第1-14天12 mg）和化疗，彭普利单抗+化疗，或彭普利单抗+安洛替尼，随后进行手术和匹配的辅助治疗。主要终点是研究者评估的主要病理反应（MPR）率。在2021年12月3日至2024年1月23日期间，90名患者被随机分配到penpulimab + anlotinib +化疗组（n = 30）、penpulimab +化疗组（n = 30）或penpulimab + anlotinib组（n = 30）。最终手术率分别为92.6%、89.7%和70.0%。在接受手术的患者中，泮普利单抗+安洛替尼+化疗组的MPR和病理完全缓解率分别为76.0% （95% CI 54.9-90.6）和52.0% (95% CI 31.3-72.2)；彭普利单抗加化疗组分别为57.7% （95% CI 36.9-76.7）和50.0% (95% CI 29.9-70.1)；彭普利单抗加安洛替尼组分别为52.4% （95% CI 29.8-74.3）和38.1% （95% CI 18.1-61.6）。在所有治疗阶段，≥3级治疗相关不良事件的发生率分别为26.7%、20.0%和30.0%。在可切除的非小细胞肺癌患者中，Penpulimab + anlotinib联合或不联合新辅助化疗显示出良好的疗效和可控的安全性，这表明它有可能成为一种可行的围手术期治疗选择。
{"title":"Perioperative penpulimab-based combination therapy in patients with resectable non-small cell lung cancer (ALTER-L043): an open-label, multicenter, randomized, phase II trial.","authors":"Meng Wang,Weiran Liu,Hongbo Guo,Hao Long,Bentong Yu,Guofang Zhao,Jun Wu,Dongsheng Yue,Xiaoliang Zhao,Chenguang Li,Lianmin Zhang,Shengguang Wang,Qiang Zhang,Zhenfa Zhang,Changli Wang","doi":"10.1038/s41392-025-02544-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02544-w","url":null,"abstract":"Although perioperative immunotherapy combined with neoadjuvant chemotherapy has improved the clinical outcomes of patients with resectable non-small cell lung cancer (NSCLC), the optimal combination strategy remains unknown. This multicenter, open-label, randomized, phase II trial (ALTER-L043; NCT04846634) evaluated the efficacy and safety of perioperative penpulimab plus anlotinib with or without neoadjuvant chemotherapy in patients with resectable NSCLC. Eligible patients were randomly assigned (1:1:1) to receive 3-4 cycles of neoadjuvant penpulimab (200 mg on day 1) plus anlotinib (12 mg on days 1-14) and chemotherapy, penpulimab plus chemotherapy, or penpulimab plus anlotinib, followed by surgery and matching adjuvant therapy. The primary endpoint was the investigator-assessed major pathologic response (MPR) rate. Between December 3, 2021, and January 23, 2024, 90 patients were randomly assigned to the penpulimab plus anlotinib and chemotherapy (n = 30), penpulimab plus chemotherapy (n = 30), or penpulimab plus anlotinib (n = 30) groups. Definitive surgery was performed in 92.6%, 89.7%, and 70.0% of patients, respectively. Among those who underwent surgery, the MPR and pathological complete response rates were 76.0% (95% CI 54.9-90.6) and 52.0% (95% CI 31.3-72.2), respectively, in the penpulimab plus anlotinib and chemotherapy group; 57.7% (95% CI 36.9-76.7) and 50.0% (95% CI 29.9-70.1), respectively, in the penpulimab plus chemotherapy group; and 52.4% (95% CI 29.8-74.3) and 38.1% (95% CI 18.1-61.6), respectively, in the penpulimab plus anlotinib group. Across all treatment phases, the incidences of grade ≥3 treatment-related adverse events were 26.7%, 20.0%, and 30.0%, respectively. Penpulimab plus anlotinib with or without neoadjuvant chemotherapy demonstrated promising efficacy and a manageable safety profile in patients with resectable NSCLC, suggesting its potential as a viable perioperative treatment option.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"52 1","pages":"21"},"PeriodicalIF":39.3,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986329","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}
Pub Date : 2026-01-16DOI: 10.1038/s41392-025-02559-3
Baldev Singh,Pankaj Gaur,Pritha Bose,Yanjun Zhang,Yaoxiang Li,Zihao Zhang,Jeyalakshmi Kandhavelu,William Klotzbier,Meth Jayatilake,Shivani Bansal,Mohd Farhan,Sunain Deol,Partha P Banerjee,Keith Unger,Seema Gupta,Vivek Verma,Amrita K Cheema
Reprogramming the immunosuppressive milieu in pancreatic cancer (PaCa) remains an important yet unmet therapeutic goal. Although tumor-associated macrophages (TAMs) are known to promote tumor growth and metastasis, little is known about the underlying mechanisms driving macrophage plasticity in PaCa. Herein, we show that extracellular vesicles (EVs) released by PaCa cells as well as circulating EVs in patient plasma, facilitate cellular crosstalk thereby promoting preferential skewing of recipient macrophages towards an M2-like TAM phenotype. PaCa-EV educated macrophages predominantly secrete anti-inflammatory cytokines, adapt an M2-like metabolic phenotype, have a higher expression of PD-L1, and suppress the proliferation of CD8+ T cells. An increased payload of miR-182-5p in PaCa-EV cargo causes a decrease in TLR4 expression in recipient macrophages and a concomitant upregulation of JAK/STAT3 pathway and elevated secretion of IL-10 and TGF-β, leading to increased PD-L1 expression. Most notably, targeted therapeutic delivery of antagomiR-182-5p in pancreatic tumor-bearing mice with varying immunogenic potential results in a significant decrease in tumor volume, increased survival, restoration of M1/M2 ratio, and an overall increase in CD8+ T cell activation in the TME. Taken together, we demonstrate a direct role of EVs in subverting the immune microenvironment and altering macrophage plasticity in a manner conducive to both tumor growth and proliferation. As such, a targeted delivery of microRNA inhibitors as drugs for altering macrophage plasticity may likely achieve better therapeutic response in pancreatic tumors.
{"title":"Extracellular vesicle-derived miRNA-182-5p educates macrophages towards an immunosuppressive phenotype in pancreatic cancer.","authors":"Baldev Singh,Pankaj Gaur,Pritha Bose,Yanjun Zhang,Yaoxiang Li,Zihao Zhang,Jeyalakshmi Kandhavelu,William Klotzbier,Meth Jayatilake,Shivani Bansal,Mohd Farhan,Sunain Deol,Partha P Banerjee,Keith Unger,Seema Gupta,Vivek Verma,Amrita K Cheema","doi":"10.1038/s41392-025-02559-3","DOIUrl":"https://doi.org/10.1038/s41392-025-02559-3","url":null,"abstract":"Reprogramming the immunosuppressive milieu in pancreatic cancer (PaCa) remains an important yet unmet therapeutic goal. Although tumor-associated macrophages (TAMs) are known to promote tumor growth and metastasis, little is known about the underlying mechanisms driving macrophage plasticity in PaCa. Herein, we show that extracellular vesicles (EVs) released by PaCa cells as well as circulating EVs in patient plasma, facilitate cellular crosstalk thereby promoting preferential skewing of recipient macrophages towards an M2-like TAM phenotype. PaCa-EV educated macrophages predominantly secrete anti-inflammatory cytokines, adapt an M2-like metabolic phenotype, have a higher expression of PD-L1, and suppress the proliferation of CD8+ T cells. An increased payload of miR-182-5p in PaCa-EV cargo causes a decrease in TLR4 expression in recipient macrophages and a concomitant upregulation of JAK/STAT3 pathway and elevated secretion of IL-10 and TGF-β, leading to increased PD-L1 expression. Most notably, targeted therapeutic delivery of antagomiR-182-5p in pancreatic tumor-bearing mice with varying immunogenic potential results in a significant decrease in tumor volume, increased survival, restoration of M1/M2 ratio, and an overall increase in CD8+ T cell activation in the TME. Taken together, we demonstrate a direct role of EVs in subverting the immune microenvironment and altering macrophage plasticity in a manner conducive to both tumor growth and proliferation. As such, a targeted delivery of microRNA inhibitors as drugs for altering macrophage plasticity may likely achieve better therapeutic response in pancreatic tumors.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"10 1","pages":"31"},"PeriodicalIF":39.3,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986331","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}
Pub Date : 2026-01-16DOI: 10.1038/s41392-025-02563-7
Philipp Hafner, Steffen J Keller, Xun Chen, Asma Alrawashdeh, Huda Jumaa, Friederike I Nollmann, Solène Besson, Judith Kemming, Oliver Gorka, Tonmoy Das, Bismark Appiah, Ariane Lehmann, Mujia Li, Petya Apostolova, Bertram Bengsch, Robert Zeiser, Stefan Tholen, Oliver Schilling, Olaf Groß, Andreas Vlachos, Uwe A Wittel, Dominik von Elverfeldt, Wilfried Reichardt, Melanie Boerries, Geoffroy Andrieux, Guus J Heynen, Stefan Fichtner-Feigl, Luciana Hannibal, Dietrich A Ruess
Oncogenic KRAS mutations drive metabolic reprogramming in pancreatic ductal adenocarcinoma (PDAC). Src-homology 2 domain-containing phosphatase 2 (SHP2) is essential for full KRAS activity, and promising dual SHP2/mitogen-activated protein kinase (MAPK) inhibition is currently being tested in clinical trials. Exploitable metabolic adaptations may contribute to invariably evolving resistance. To understand the metabolic changes induced by dual inhibition, we comprehensively tested human and murine PDAC cell lines, endogenous tumor models, and patient-derived organoids, which are representative of the full spectrum of PDAC molecular subtypes. We found that dual SHP2/mitogen-activated protein kinase kinase (MEK1/2) inhibition induces major alterations in mitochondrial mass and function, impacts reactive oxygen species (ROS) homeostasis and triggers lipid peroxidase dependency. Anabolic pathways, autophagy and glycolysis were also profoundly altered. However, most strikingly, mitochondrial remodeling was evident, persisting into a therapy-resistant state. The resulting vulnerability to the induction of ferroptotic cell death via the combination of vertical SHP2/MEK1/2 with glutathione peroxidase (GPX4) inhibition was largely independent of the PDAC molecular subtype and was confirmed with direct targeting of RAS. The triple combination of SHP2/MEK1/2 inhibition and the ferroptosis-inducing natural compound withaferin A suppressed tumor progression in an endogenous PDAC tumor model in vivo. Our study offers a metabolic leverage point to reinforce RAS pathway interference for targeted PDAC treatment.
{"title":"Vertical RAS pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations.","authors":"Philipp Hafner, Steffen J Keller, Xun Chen, Asma Alrawashdeh, Huda Jumaa, Friederike I Nollmann, Solène Besson, Judith Kemming, Oliver Gorka, Tonmoy Das, Bismark Appiah, Ariane Lehmann, Mujia Li, Petya Apostolova, Bertram Bengsch, Robert Zeiser, Stefan Tholen, Oliver Schilling, Olaf Groß, Andreas Vlachos, Uwe A Wittel, Dominik von Elverfeldt, Wilfried Reichardt, Melanie Boerries, Geoffroy Andrieux, Guus J Heynen, Stefan Fichtner-Feigl, Luciana Hannibal, Dietrich A Ruess","doi":"10.1038/s41392-025-02563-7","DOIUrl":"10.1038/s41392-025-02563-7","url":null,"abstract":"<p><p>Oncogenic KRAS mutations drive metabolic reprogramming in pancreatic ductal adenocarcinoma (PDAC). Src-homology 2 domain-containing phosphatase 2 (SHP2) is essential for full KRAS activity, and promising dual SHP2/mitogen-activated protein kinase (MAPK) inhibition is currently being tested in clinical trials. Exploitable metabolic adaptations may contribute to invariably evolving resistance. To understand the metabolic changes induced by dual inhibition, we comprehensively tested human and murine PDAC cell lines, endogenous tumor models, and patient-derived organoids, which are representative of the full spectrum of PDAC molecular subtypes. We found that dual SHP2/mitogen-activated protein kinase kinase (MEK1/2) inhibition induces major alterations in mitochondrial mass and function, impacts reactive oxygen species (ROS) homeostasis and triggers lipid peroxidase dependency. Anabolic pathways, autophagy and glycolysis were also profoundly altered. However, most strikingly, mitochondrial remodeling was evident, persisting into a therapy-resistant state. The resulting vulnerability to the induction of ferroptotic cell death via the combination of vertical SHP2/MEK1/2 with glutathione peroxidase (GPX4) inhibition was largely independent of the PDAC molecular subtype and was confirmed with direct targeting of RAS. The triple combination of SHP2/MEK1/2 inhibition and the ferroptosis-inducing natural compound withaferin A suppressed tumor progression in an endogenous PDAC tumor model in vivo. Our study offers a metabolic leverage point to reinforce RAS pathway interference for targeted PDAC treatment.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":"33"},"PeriodicalIF":52.7,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12811380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990661","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}
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis, particularly in the presence of liver metastases. The mechanisms by which metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), influences PDAC progression and metastasis remain poorly understood. This study investigates the role of MASLD in fostering an immunosuppressive microenvironment conducive to PDAC liver metastases and identifies the macrophage migration inhibitory factor (MIF)-CD44 axis as a key mediator of this process. Utilizing data from the UK Biobank (450,754 participants, median follow-up 14.5 years), we observed an overall increased risk of PDAC in the MASLD population (HR: 3.48; 95% CI: 2.69-4.50; P < 0.0001). Clinical cohorts confirmed the strong association between MASLD and hepatic metastases (OR: 7.06; 95% CI: 4.62-10.78; P < 0.0001). Experimental mouse models demonstrated that MASLD enhances tumor cell stemness, immune evasion, and focal adhesion in metastatic liver tissues. Mechanistically, MASLD-induced MIF secretion promotes CD44-positive PDAC cell migration, stemness, and adhesion. Targeting MIF, either genetically or pharmacologically using the MIF tautomerase inhibitor IPG1576 significantly attenuated liver metastasis in preclinical models. Validation in patient samples revealed elevated hepatic MIF and CD44 expression in MASLD-associated PDAC liver metastases. This study highlights the MIF-CD44 axis as a promising therapeutic target and underscores the importance of tailoring treatments for PDAC patients with concurrent MASLD.
胰腺导管腺癌（PDAC）是一种高度侵袭性的恶性肿瘤，预后差，特别是存在肝转移。代谢功能障碍相关的脂肪性肝病（MASLD），以前称为非酒精性脂肪性肝病（NAFLD），影响PDAC进展和转移的机制仍然知之甚少。本研究探讨了MASLD在培养有利于PDAC肝转移的免疫抑制微环境中的作用，并确定巨噬细胞迁移抑制因子(MIF)-CD44轴是这一过程的关键中介。利用英国生物银行（UK Biobank）的数据（450,754名参与者，中位随访14.5年），我们观察到MASLD人群PDAC的总体风险增加（HR: 3.48; 95% CI: 2.69-4.50; P < 0.0001）。临床队列证实了MASLD与肝转移之间的强相关性（OR: 7.06; 95% CI: 4.62-10.78; P < 0.0001）。实验小鼠模型表明，MASLD增强肿瘤细胞的干性、免疫逃逸和转移性肝组织的局灶黏附。从机制上讲，masld诱导的MIF分泌促进了cd44阳性PDAC细胞的迁移、干性和粘附。在临床前模型中，以MIF为靶点，在基因或药理学上使用MIF变异体酶抑制剂IPG1576可显著减轻肝转移。患者样本的验证显示，在masld相关的PDAC肝转移中，肝脏MIF和CD44表达升高。这项研究强调了MIF-CD44轴作为一个有希望的治疗靶点，并强调了对合并MASLD的PDAC患者进行定制治疗的重要性。
{"title":"Metabolic dysfunction-associated steatotic liver disease accelerates pancreatic cancer progression and metastasis via the macrophage migration inhibitory factor-CD44 axis.","authors":"Qian Yu,Hui Song,Xiao-Ya Shi,Liang Zhu,Yu Liang,Rui-Ning Gong,Xiao-Wu Dong,Shang-Long Liu,Hai-Zhen Wang,Ying-Luo Wang,Jiu-Fa Cui,Xiao-Nan Yang,Ying Chen,Chao Gao,Zhan Yang,Qing-Tian Zhu,Chang Li,Huan Zhang,Jie-Er Ying,Mei-Fang Zheng,Yan-Tao Tian,Hai-Tao Hu,Xin-Xin Shao,Yue Li,Ming-Guang Mo,Yun Lu,Zheng Ma,Shun-Li Fu,Qing-Hui Niu,Yuan-Yu Liao,Chen-Yang Zhao,Xin Liu,Ashok K Saluja,Ji-Gang Wang,Xiao-Yu Li,Song-Yue Guo,Wei-Hua Wang,Song Wang,Bin Liu,Guo-Tao Lu,He Ren","doi":"10.1038/s41392-025-02562-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02562-8","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis, particularly in the presence of liver metastases. The mechanisms by which metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), influences PDAC progression and metastasis remain poorly understood. This study investigates the role of MASLD in fostering an immunosuppressive microenvironment conducive to PDAC liver metastases and identifies the macrophage migration inhibitory factor (MIF)-CD44 axis as a key mediator of this process. Utilizing data from the UK Biobank (450,754 participants, median follow-up 14.5 years), we observed an overall increased risk of PDAC in the MASLD population (HR: 3.48; 95% CI: 2.69-4.50; P < 0.0001). Clinical cohorts confirmed the strong association between MASLD and hepatic metastases (OR: 7.06; 95% CI: 4.62-10.78; P < 0.0001). Experimental mouse models demonstrated that MASLD enhances tumor cell stemness, immune evasion, and focal adhesion in metastatic liver tissues. Mechanistically, MASLD-induced MIF secretion promotes CD44-positive PDAC cell migration, stemness, and adhesion. Targeting MIF, either genetically or pharmacologically using the MIF tautomerase inhibitor IPG1576 significantly attenuated liver metastasis in preclinical models. Validation in patient samples revealed elevated hepatic MIF and CD44 expression in MASLD-associated PDAC liver metastases. This study highlights the MIF-CD44 axis as a promising therapeutic target and underscores the importance of tailoring treatments for PDAC patients with concurrent MASLD.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"19 1","pages":"32"},"PeriodicalIF":39.3,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986332","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}
Pub Date : 2026-01-15DOI: 10.1038/s41392-025-02543-x
Choong-Jae Lee,Hyeon-Ji Yun,Tae-Young Jang,So-El Jeon,Yeong-Hoon Cho,Da-Ye Lim,Eun-Ju Han,Sun-Young Kong,Jeong-Seok Nam
The tumor microenvironment (TME) plays a central role in cancer progression and metastasis. A key feature of the TME is extracellular acidity, which promotes disease progression, immune evasion, and drug resistance. Tumor acidity is increasingly recognized as a critical factor in cancer development and a negative prognostic indicator. Here, we demonstrate that the membrane glycoprotein dysadherin promotes colorectal cancer (CRC) malignancy by modulating TME acidity. Comprehensive bioinformatics and pathological analyses of CRC patient samples revealed that increased tumor acidity is a hallmark of CRC progression and strongly correlates with high expression of dysadherin. Functional studies confirmed that dysadherin enhances malignant traits, particularly under acidic conditions. Mechanistically, dysadherin activates the integrin/FAK/STAT3 signaling pathway, leading to the upregulation of carbonic anhydrase 9 (CA9). CA9 facilitates proton export, contributing to extracellular acidification while maintaining intracellular pH homeostasis, thereby enabling cancer cells to survive and thrive in acidic environments. In a murine liver metastasis model, dysadherin deletion impaired cellular adaptation to the acidic TME and markedly attenuated metastatic colonization, whereas restoring CA9 expression effectively rescued metastatic potential. Overall, our findings identify the dysadherin/CA9 axis as a potential therapeutic target in CRC and provide new insights into how tumors exploit acidosis to drive malignant development and progression.
{"title":"The dysadherin/carbonic anhydrase 9 axis shapes an acidic tumor microenvironment to promote colorectal cancer progression.","authors":"Choong-Jae Lee,Hyeon-Ji Yun,Tae-Young Jang,So-El Jeon,Yeong-Hoon Cho,Da-Ye Lim,Eun-Ju Han,Sun-Young Kong,Jeong-Seok Nam","doi":"10.1038/s41392-025-02543-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02543-x","url":null,"abstract":"The tumor microenvironment (TME) plays a central role in cancer progression and metastasis. A key feature of the TME is extracellular acidity, which promotes disease progression, immune evasion, and drug resistance. Tumor acidity is increasingly recognized as a critical factor in cancer development and a negative prognostic indicator. Here, we demonstrate that the membrane glycoprotein dysadherin promotes colorectal cancer (CRC) malignancy by modulating TME acidity. Comprehensive bioinformatics and pathological analyses of CRC patient samples revealed that increased tumor acidity is a hallmark of CRC progression and strongly correlates with high expression of dysadherin. Functional studies confirmed that dysadherin enhances malignant traits, particularly under acidic conditions. Mechanistically, dysadherin activates the integrin/FAK/STAT3 signaling pathway, leading to the upregulation of carbonic anhydrase 9 (CA9). CA9 facilitates proton export, contributing to extracellular acidification while maintaining intracellular pH homeostasis, thereby enabling cancer cells to survive and thrive in acidic environments. In a murine liver metastasis model, dysadherin deletion impaired cellular adaptation to the acidic TME and markedly attenuated metastatic colonization, whereas restoring CA9 expression effectively rescued metastatic potential. Overall, our findings identify the dysadherin/CA9 axis as a potential therapeutic target in CRC and provide new insights into how tumors exploit acidosis to drive malignant development and progression.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"48 1","pages":"19"},"PeriodicalIF":39.3,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968350","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}
Acute pancreatitis is a complex inflammatory condition characterized by sudden onset and rapid progression, with severe cases often associated with high mortality. In recent years, the global incidence of acute pancreatitis has been increasing, with marked regional differences. This increasing trend not only places a considerable burden on healthcare systems but also significantly affects the physical and psychological well-being of patients. The most common causes-gallstone disease, hypertriglyceridemia, and alcohol abuse-also vary by region. This review provides a structured summary of current knowledge regarding the definition and classification of acute pancreatitis, along with recent advances in clinical scoring systems, biomarkers, and predictive models based on artificial intelligence. These tools are particularly valuable for risk stratification and early clinical decision-making. In addition, this review discusses the multilevel pathophysiological mechanisms involved in acute pancreatitis, including aberrant enzymatic activation, calcium overload, impaired autophagy, inflammatory responses, and various forms of pancreatic acinar cell death. From a therapeutic perspective, both early-phase management and strategies for later disease stages are addressed. This review also briefly assesses adjunctive therapies rooted in traditional Chinese medicine, including bioactive monomers, compound herbal formulas, and external treatment modalities. Furthermore, attention is given to individualized treatment approaches for special populations, as well as to emerging therapeutic avenues such as nanotechnology and extracellular vesicle-based interventions. Together, these insights serve as a comprehensive reference for the diagnosis and management of acute pancreatitis while also suggesting potential directions for future research and innovation.
{"title":"Acute pancreatitis: mechanisms and therapeutic approaches.","authors":"Qian Hu,Yue Hu,Chunlu Tan,Yue Yang,Hang Su,Zixing Huang,Wenfu Tang,Rui Wang,Jingping Liu,Meihua Wan","doi":"10.1038/s41392-025-02394-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02394-6","url":null,"abstract":"Acute pancreatitis is a complex inflammatory condition characterized by sudden onset and rapid progression, with severe cases often associated with high mortality. In recent years, the global incidence of acute pancreatitis has been increasing, with marked regional differences. This increasing trend not only places a considerable burden on healthcare systems but also significantly affects the physical and psychological well-being of patients. The most common causes-gallstone disease, hypertriglyceridemia, and alcohol abuse-also vary by region. This review provides a structured summary of current knowledge regarding the definition and classification of acute pancreatitis, along with recent advances in clinical scoring systems, biomarkers, and predictive models based on artificial intelligence. These tools are particularly valuable for risk stratification and early clinical decision-making. In addition, this review discusses the multilevel pathophysiological mechanisms involved in acute pancreatitis, including aberrant enzymatic activation, calcium overload, impaired autophagy, inflammatory responses, and various forms of pancreatic acinar cell death. From a therapeutic perspective, both early-phase management and strategies for later disease stages are addressed. This review also briefly assesses adjunctive therapies rooted in traditional Chinese medicine, including bioactive monomers, compound herbal formulas, and external treatment modalities. Furthermore, attention is given to individualized treatment approaches for special populations, as well as to emerging therapeutic avenues such as nanotechnology and extracellular vesicle-based interventions. Together, these insights serve as a comprehensive reference for the diagnosis and management of acute pancreatitis while also suggesting potential directions for future research and innovation.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"259 1","pages":"15"},"PeriodicalIF":39.3,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961276","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}
The dynamic interplay between neoplastic cells and the host has been increasingly recognized as important players in the pathogenesis of cancer cachexia, a syndrome affecting ~50-80% of cancer patients with various incidences of different types of malignancies. Despite its prevalence, a comprehensive understanding of cancer cachexia progression, with a holistic view at the cross-organismal, cellular and molecular levels, remains elusive. In this review, we undertake an in-depth exploration of the relevant target organs and their regulatory roles in cancer cachexia, with a particular focus on macroenvironmental interactions via various organismal crosstalk axes. Moreover, we highlight how systemic metabolic remodeling, a hallmark of cancer cachexia, plays essential roles in modulating the inflammatory responses of immune and stromal cells in the tumor microenvironment (TME). These cellular responses, in turn, disrupt energy metabolism in distant organs and perturb organismal homeostasis by secreting a variety of mediators that activate specific signaling pathways, thereby fostering a vicious cycle that exacerbates cancer cachexia. We comprehensively summarize these complex cellular and molecular networks that constitute reciprocally regulatory dynamics between systemic metabolic reprogramming and inflammatory cascades. Notably, targeting the multifaceted interplay of organismal metabolic remodeling and cancer-associated inflammation holds great promise for clinical translation, as illustrated by a series of innovative therapeutic strategies and ongoing clinical trials aimed at mitigating cachexia in cancer patients.
{"title":"Cancer cachexia: molecular basis and therapeutic advances.","authors":"Yuting Tan,Rui Xue,Yuwei Pan,Zongsheng He,Xiao Hu,Yaping Li,Ke Li,Xuan Zhang,Xiu-Wu Bian,Bin Wang","doi":"10.1038/s41392-025-02331-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02331-7","url":null,"abstract":"The dynamic interplay between neoplastic cells and the host has been increasingly recognized as important players in the pathogenesis of cancer cachexia, a syndrome affecting ~50-80% of cancer patients with various incidences of different types of malignancies. Despite its prevalence, a comprehensive understanding of cancer cachexia progression, with a holistic view at the cross-organismal, cellular and molecular levels, remains elusive. In this review, we undertake an in-depth exploration of the relevant target organs and their regulatory roles in cancer cachexia, with a particular focus on macroenvironmental interactions via various organismal crosstalk axes. Moreover, we highlight how systemic metabolic remodeling, a hallmark of cancer cachexia, plays essential roles in modulating the inflammatory responses of immune and stromal cells in the tumor microenvironment (TME). These cellular responses, in turn, disrupt energy metabolism in distant organs and perturb organismal homeostasis by secreting a variety of mediators that activate specific signaling pathways, thereby fostering a vicious cycle that exacerbates cancer cachexia. We comprehensively summarize these complex cellular and molecular networks that constitute reciprocally regulatory dynamics between systemic metabolic reprogramming and inflammatory cascades. Notably, targeting the multifaceted interplay of organismal metabolic remodeling and cancer-associated inflammation holds great promise for clinical translation, as illustrated by a series of innovative therapeutic strategies and ongoing clinical trials aimed at mitigating cachexia in cancer patients.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"27 1","pages":"16"},"PeriodicalIF":39.3,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956203","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}
Vascular smooth muscle cell (VSMC) degeneration is a major mechanism underlying abdominal aortic aneurysm (AAA) formation. However, the upstream signaling pathways that converge on the transcriptional machinery to drive VSMC degeneration remain elusive. Here, we integrated single-nucleus (sn) multi-omics, chromatin immunoprecipitation (ChIP)-seq, and wet lab validation to identify transcriptional effectors of VSMC-MAPK14, which we previously reported to promote AAA. Compared with wild-type (WT) mice, VSMC-Mapk14 knockout (KO) mice displayed reduced VSMC degeneration, as evidenced by decreased expression of markers of endoplasmic reticulum stress, the unfolded protein response, fibrosis, and apoptosis, after 7 days of Ang II infusion. SnRNA-seq revealed increased VSMCs and reduced fibroblast and immune cell populations in KOs. Reclustering VSMCs revealed an increased proportion of contractile cluster and a reduced proportion of fibrotic cluster in KOs. The VSMC differentiation gene program and upstream pathways were upregulated, whereas degeneration pathways, including extracellular matrix remodeling, inflammation, and apoptosis, were downregulated in KO VSMCs. snATAC-seq and validation revealed increased serum response factor (SRF) motif activity and expression but reduced RUNX2 expression in KO VSMCs. Integrative analysis of snATAC-seq, ChIP-seq, and bulk RNA-seq identified the MYOCD/SRF/CArG triad as the driver of the contractile gene program following Mapk14 loss. We further found that the expression of Bcl2, a novel MYOCD/SRF/CArG target, was increased in Mapk14 KO VSMCs. Loss of Mapk14 attenuated MRTFA protein abundance via increased ubiquitin‒proteasome degradation, which was attributed to reduced USP10 protein expression. These findings reveal MAPK14-driven transcriptomic and epigenomic landscapes that promote VSMC degeneration by suppressing SRF/MYOCD/CArG while activating RUNX2 and MRTFA. Our study provides mechanistic insight into MAPK14-mediated VSMC degeneration and provides a basis for MAPK14-targeted therapeutic strategies for AAA.
血管平滑肌细胞（VSMC）变性是腹主动脉瘤（AAA）形成的主要机制。然而，聚合在转录机制上驱动VSMC变性的上游信号通路仍然难以捉摸。在这里，我们整合了单核（sn）多组学、染色质免疫沉淀(ChIP)-seq和湿实验室验证来鉴定VSMC- mapk14的转录效应物，我们之前报道过VSMC- mapk14促进AAA。与野生型（WT）小鼠相比，VSMC- mapk14敲除（KO）小鼠在输注Ang II 7天后，内质网应激标记物、未折叠蛋白反应、纤维化和凋亡的表达减少。SnRNA-seq显示，KOs中VSMCs增加，成纤维细胞和免疫细胞数量减少。重新聚类的VSMCs显示，在KOs中，收缩簇的比例增加，纤维化簇的比例减少。在KO VSMC中，VSMC分化基因程序和上游通路上调，而包括细胞外基质重塑、炎症和凋亡在内的变性通路下调。snATAC-seq和验证显示，KO VSMCs中血清反应因子（SRF）基序活性和表达增加，但RUNX2表达降低。对snATAC-seq、ChIP-seq和bulk RNA-seq的综合分析发现，心肌/SRF/CArG三联体是Mapk14缺失后收缩基因程序的驱动因素。我们进一步发现，Bcl2（一种新的心肌/SRF/CArG靶点）在Mapk14 KO VSMCs中的表达增加。Mapk14的缺失通过增加泛素蛋白酶体降解降低了MRTFA蛋白的丰度，这归因于USP10蛋白表达的降低。这些发现揭示了mapk14驱动的转录组和表观基因组景观通过抑制SRF/心肌/CArG而激活RUNX2和MRTFA来促进VSMC变性。我们的研究提供了mapk14介导的VSMC变性的机制，并为针对mapk14的AAA治疗策略提供了基础。
{"title":"MAPK14 converges on key transcriptional machinery to promote vascular smooth muscle cell degeneration in abdominal aortic aneurysm.","authors":"Xiaoliang Wu,Chunhui Wang,Nestor Ishimwe,Wei Zhang,Jaser Doja,Shengshuai Shan,Chunyu Ge,Yong Sun,Jinjing Zhao,Micah Castillo,Peter Sotonyi,Gergo Gyurok,Gabor Csanyi,W Bart Bryant,Kunzhe Dong,Yabing Chen,Roberto Vazquez-Padron,Joseph M Miano,Xiaochun Long","doi":"10.1038/s41392-025-02540-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02540-0","url":null,"abstract":"Vascular smooth muscle cell (VSMC) degeneration is a major mechanism underlying abdominal aortic aneurysm (AAA) formation. However, the upstream signaling pathways that converge on the transcriptional machinery to drive VSMC degeneration remain elusive. Here, we integrated single-nucleus (sn) multi-omics, chromatin immunoprecipitation (ChIP)-seq, and wet lab validation to identify transcriptional effectors of VSMC-MAPK14, which we previously reported to promote AAA. Compared with wild-type (WT) mice, VSMC-Mapk14 knockout (KO) mice displayed reduced VSMC degeneration, as evidenced by decreased expression of markers of endoplasmic reticulum stress, the unfolded protein response, fibrosis, and apoptosis, after 7 days of Ang II infusion. SnRNA-seq revealed increased VSMCs and reduced fibroblast and immune cell populations in KOs. Reclustering VSMCs revealed an increased proportion of contractile cluster and a reduced proportion of fibrotic cluster in KOs. The VSMC differentiation gene program and upstream pathways were upregulated, whereas degeneration pathways, including extracellular matrix remodeling, inflammation, and apoptosis, were downregulated in KO VSMCs. snATAC-seq and validation revealed increased serum response factor (SRF) motif activity and expression but reduced RUNX2 expression in KO VSMCs. Integrative analysis of snATAC-seq, ChIP-seq, and bulk RNA-seq identified the MYOCD/SRF/CArG triad as the driver of the contractile gene program following Mapk14 loss. We further found that the expression of Bcl2, a novel MYOCD/SRF/CArG target, was increased in Mapk14 KO VSMCs. Loss of Mapk14 attenuated MRTFA protein abundance via increased ubiquitin‒proteasome degradation, which was attributed to reduced USP10 protein expression. These findings reveal MAPK14-driven transcriptomic and epigenomic landscapes that promote VSMC degeneration by suppressing SRF/MYOCD/CArG while activating RUNX2 and MRTFA. Our study provides mechanistic insight into MAPK14-mediated VSMC degeneration and provides a basis for MAPK14-targeted therapeutic strategies for AAA.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"49 1","pages":"17"},"PeriodicalIF":39.3,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956025","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}
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