Pub Date : 2026-02-06DOI: 10.1016/j.tranon.2026.102690
Venkatesh Rajamanickam , Noah D. Simons , Wesley Rosales , Anton Kravchenko , Tomoko Yamazaki , Brady Bernard , Brian Piening , Enric Domingo , Timothy Maughan , Charlems Alvarez-Jimenez , Thomas Desilvio , Satish Viswanath , Mark Whiteford , Amanda Hayman , David O’Brien , Maria X. Kiely , Rehan Ahmad , Michael J. Gough , Marka R. Crittenden , Kristina H. Young
Improving responses to neoadjuvant therapy for patients with locally advanced rectal cancer has the potential to improve organ preservation and disease-free survival. Knowing which patients may need therapeutic escalation or de-escalation from standard-of-care treatment remains an area of investigation. We previously reported the primary and secondary endpoints of our single-arm study combining transforming growth factor beta receptor inhibitor, Galunisertib, with neoadjuvant chemoradiation in patients with locally advanced rectal cancer. Here we analyze RNA sequencing data obtained from tissue biopsies at baseline and after 2 weeks of galunisertib. Differences in expression of genes associated with MYC, inflammation, and epithelial-to-mesenchymal transition were observed between complete responders (CR) and <CR, with galunisertib upregulating MYC pathway expression in CR. Radiosensitivity and TGFβ response scores demonstrated limited ability to predict for response to galunisertib + chemoradiation. Typically treatment-resistant consensus molecular subtype 4 (CMS4), characterized by TGFβ expression, and metabolic subtype (CMS3) were associated with response to galunisertib + chemoradiation. Differences in correlations between RNA based measures of cell composition and immunohistologic quantification of infiltrates and extracted MRI parameters were observed for CIBERSORT, MCPcounter, and xCell methodologies. Based on these data, we hypothesize that the stromal radioresistant phenotype driven by TGFβ can be overcome by the addition of galunisertib to chemoradiation in rectal cancer.
{"title":"CMS subtypes correlate with complete response in trial of neoadjuvant Galunisertib plus chemoradiation in rectal cancer","authors":"Venkatesh Rajamanickam , Noah D. Simons , Wesley Rosales , Anton Kravchenko , Tomoko Yamazaki , Brady Bernard , Brian Piening , Enric Domingo , Timothy Maughan , Charlems Alvarez-Jimenez , Thomas Desilvio , Satish Viswanath , Mark Whiteford , Amanda Hayman , David O’Brien , Maria X. Kiely , Rehan Ahmad , Michael J. Gough , Marka R. Crittenden , Kristina H. Young","doi":"10.1016/j.tranon.2026.102690","DOIUrl":"10.1016/j.tranon.2026.102690","url":null,"abstract":"<div><div>Improving responses to neoadjuvant therapy for patients with locally advanced rectal cancer has the potential to improve organ preservation and disease-free survival. Knowing which patients may need therapeutic escalation or de-escalation from standard-of-care treatment remains an area of investigation. We previously reported the primary and secondary endpoints of our single-arm study combining transforming growth factor beta receptor inhibitor, Galunisertib, with neoadjuvant chemoradiation in patients with locally advanced rectal cancer. Here we analyze RNA sequencing data obtained from tissue biopsies at baseline and after 2 weeks of galunisertib. Differences in expression of genes associated with MYC, inflammation, and epithelial-to-mesenchymal transition were observed between complete responders (CR) and <CR, with galunisertib upregulating <em>MYC</em> pathway expression in CR. Radiosensitivity and TGFβ response scores demonstrated limited ability to predict for response to galunisertib + chemoradiation. Typically treatment-resistant consensus molecular subtype 4 (CMS4), characterized by TGFβ expression, and metabolic subtype (CMS3) were associated with response to galunisertib + chemoradiation. Differences in correlations between RNA based measures of cell composition and immunohistologic quantification of infiltrates and extracted MRI parameters were observed for CIBERSORT, MCPcounter, and xCell methodologies. Based on these data, we hypothesize that the stromal radioresistant phenotype driven by TGFβ can be overcome by the addition of galunisertib to chemoradiation in rectal cancer.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"66 ","pages":"Article 102690"},"PeriodicalIF":5.0,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146122687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
WNT1 inducible signaling pathway protein 1 (WISP1) is a connective tissue growth factor that regulates various cellular functions in different tissues but has yet to be examined in the human bladder. Two isoforms of WISP1 (WISP1v1 and WISP1v2) expressed only in bladder fibroblast (HBdSF) and smooth muscle (HBdSMC) cells but not in bladder cancer cells in vitro. TNF-α treatment-induced IL-6, CXCL5, and SDF-1 expressions in bladder stroma cells. TNF-α-induced IL-6 depends on the WISP1, and the TNF-α-activation was suppressed under CAPE treatment. WISP1-knockdown inhibited the proliferation and contraction of HBdSMC and HBdSF cells, while the conditioned media from either ectopic WISP1v1- or WISP1v2-overexpressed 293T cells stimulated both the proliferation of HBdSF and HBdSMC cells. The supernatant of WISP1-knockdown in HBdSMC cells reduced the migration of bladder carcinoma T24 cells. WISP1v1, but not WISP1v2, enhanced cell growth, migration, and invasion in bladder cancer cells via downregulating NDRG1, KAI1, and Maspin expressions. Silico's analysis confirmed that WISP1 is a potential oncogene in human bladder cancer. Results suggest that WISP1, a stroma-specific secreted protein, modulates the behavior of bladder stroma cells via autocrine signaling. WISP1 induces tumor growth of bladder carcinoma cells in an isoform-dependent manner via paracrine signaling, indicating that WISP1 may behave as a mediator linking diseases of the human bladder.
{"title":"WISP1 is the stromal-secreting oncoprotein via paracrine downregulation of NDRG1, KAI1, and Maspin in human bladder cancer cells","authors":"Syue-Ting Chen , Kang-Shuo Chang , Chen-Pang Hou , Wei-Yin Lin , Shu-Yuan Hsu , Hsin-Ching Sung , Tsui-Hsia Feng , Yu-Hsiang Lin , Horng-Heng Juang","doi":"10.1016/j.tranon.2026.102680","DOIUrl":"10.1016/j.tranon.2026.102680","url":null,"abstract":"<div><div>WNT1 inducible signaling pathway protein 1 (WISP1) is a connective tissue growth factor that regulates various cellular functions in different tissues but has yet to be examined in the human bladder. Two isoforms of WISP1 (WISP1v1 and WISP1v2) expressed only in bladder fibroblast (HBdSF) and smooth muscle (HBdSMC) cells but not in bladder cancer cells <em>in vitro</em>. TNF-α treatment-induced IL-6, CXCL5, and SDF-1 expressions in bladder stroma cells. TNF-α-induced IL-6 depends on the WISP1, and the TNF-α-activation was suppressed under CAPE treatment. WISP1-knockdown inhibited the proliferation and contraction of HBdSMC and HBdSF cells, while the conditioned media from either ectopic WISP1v1- or WISP1v2-overexpressed 293T cells stimulated both the proliferation of HBdSF and HBdSMC cells. The supernatant of WISP1-knockdown in HBdSMC cells reduced the migration of bladder carcinoma T24 cells. WISP1v1, but not WISP1v2, enhanced cell growth, migration, and invasion in bladder cancer cells via downregulating NDRG1, KAI1, and Maspin expressions. Silico's analysis confirmed that WISP1 is a potential oncogene in human bladder cancer. Results suggest that WISP1, a stroma-specific secreted protein, modulates the behavior of bladder stroma cells via autocrine signaling. WISP1 induces tumor growth of bladder carcinoma cells in an isoform-dependent manner via paracrine signaling, indicating that WISP1 may behave as a mediator linking diseases of the human bladder.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"65 ","pages":"Article 102680"},"PeriodicalIF":5.0,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146079445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer stem cells (CSCs) are a small subpopulation of tumor cells characterized by their self-renewal capacity and the ability to differentiate into different cell types. These partially differentiated cells exhibit properties of both stem cells and cancer cells. CSCs drive tumor initiation and progression by generating additional stem cells through self-renewal and differentiation into heterogeneous populations of tumor cell. They are among the most aggressive tumor cells that contribute to the development of key features of malignancy such as increased proliferation, metastasis, tumor growth, multidrug resistance (MDR), and resistance to radiotherapy and chemotherapy. CSCs are also associated with relapse and minimal residual disease, highlighting their critical role in cancer persistence. Therefore, targeting CSCs is essential to achieve complete tumor eradication. Available evidence suggests that combination therapies that integrate immunotherapy with cytotoxic therapies to concurrently eliminate CSCs and non-CSCs offer a promising approach to completely eradicate cancer. This review summarizes the current strategies employed to target CSCs and improve cancer treatment outcomes.
{"title":"Targeting cancer stem cells as the most aggressive and tumor-initiating cells","authors":"Maryam Sadri , Zahra Shafaghat , Mona Roozbehani , Maryam Dorfaki , Fatemeh Kheiri , Sahel Heidari , Ali Mahmoudi , Fatemeh Faraji","doi":"10.1016/j.tranon.2026.102669","DOIUrl":"10.1016/j.tranon.2026.102669","url":null,"abstract":"<div><div>Cancer stem cells (CSCs) are a small subpopulation of tumor cells characterized by their self-renewal capacity and the ability to differentiate into different cell types. These partially differentiated cells exhibit properties of both stem cells and cancer cells. CSCs drive tumor initiation and progression by generating additional stem cells through self-renewal and differentiation into heterogeneous populations of tumor cell. They are among the most aggressive tumor cells that contribute to the development of key features of malignancy such as increased proliferation, metastasis, tumor growth, multidrug resistance (MDR), and resistance to radiotherapy and chemotherapy. CSCs are also associated with relapse and minimal residual disease, highlighting their critical role in cancer persistence. Therefore, targeting CSCs is essential to achieve complete tumor eradication. Available evidence suggests that combination therapies that integrate immunotherapy with cytotoxic therapies to concurrently eliminate CSCs and non-CSCs offer a promising approach to completely eradicate cancer. This review summarizes the current strategies employed to target CSCs and improve cancer treatment outcomes.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"65 ","pages":"Article 102669"},"PeriodicalIF":5.0,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146079446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-25DOI: 10.1016/j.tranon.2026.102685
Zimin Wang , Hao Liu , Jiawei Liang , Ying Zhang , William C. Cho , Minhua Ye , Dehua Ma , Min Kong , Chengchu Zhu , Jianfei Shen
Background
The monotherapeutic efficacy of immune checkpoint inhibitors (ICIs) remains unsatisfactory in patients suffering from non-small-cell lung cancer (NSCLC). Ferroptosis, an iron-dependent cell death process, has been identified as a promising immunotherapy adjuvant; however, ferroptosis inducers (such as erastin, RSL3) may paradoxically up-regulate hypoxia-inducible factor 1α (HIF-1α) and programmed death ligand 1 (PD-L1) to propel tumor immune evasion. It is critical to explore the molecular mechanism of ferroptosis in NSCLC immunotherapy and verify the efficacy of combined regimens for overcoming ICI limitations clinically.
Methods
This work analyzed 162 NSCLC patients receiving immunotherapy retrospectively to evaluate correlation between PD-L1 expression and progression-free survival (PFS). In vitro, CCK-8 assay, flow cytometry, qPCR, and Western blotting were utilized to measure impacts of ferroptosis inducers (Erastin, RSL3) upon cell viability, reactive oxygen species (ROS) levels, and PD-L1/HIF-1α expression in A549/H1299 NSCLC cells; ferroptosis-specific effects were validated by means of iron chelators (DFO, ferrostatin-1). In vivo, subcutaneous tumor models were built in C57BL/6 mice with LLC cells; therapeutic effects of ferroptosis inducer (IKE) alone or combined with anti-PD-1 antibody were evaluated through tumor weight measurement and immunohistochemistry (IHC). HIF-1α binding to PD-L1 promoter was confirmed via chromatin immunoprecipitation (ChIP); related signaling pathways were explored using transcriptome sequencing and KEGG enrichment analysis.
Results
For NSCLC patients who received immunotherapy, high PD-L1 expression correlated with longer PFS, and 4-HNE was associated positively with PD-L1 and CD8⁺T infiltration. In vitro, Erastin/RSL3 induced dose-dependent cell death, ROS accumulation, and PD-L1 up-regulation, reversed by iron chelators. In vivo, IKE+anti-PD-1 inhibited tumor growth significantly, whereas it increased CD8⁺T infiltration. Mechanistically, Erastin up-regulated HIF-1α via PI3K-AKT, which bound PD-L1 promoter (ChIP-verified), reversed by iron chelators.
Conclusions
Ferroptosis inducers have dual effects in NSCLC, namely, promoting tumor cell death and triggering PD-L1-dependent immune evasion via the PI3K-AKT-HIF-1α pathway. However, combining ferroptosis inducers with anti-PD-1 antibodies retains the anti-tumor effect of ferroptosis and overcomes immune evasion by obstructing the PD-L1 pathway, offering a novel strategy for enhancing NSCLC immunotherapy efficacy.
{"title":"Ferroptosis induction enhances anti-PD-1 efficacy in NSCLC via HIF-1α/PD-L1 modulation","authors":"Zimin Wang , Hao Liu , Jiawei Liang , Ying Zhang , William C. Cho , Minhua Ye , Dehua Ma , Min Kong , Chengchu Zhu , Jianfei Shen","doi":"10.1016/j.tranon.2026.102685","DOIUrl":"10.1016/j.tranon.2026.102685","url":null,"abstract":"<div><h3>Background</h3><div>The monotherapeutic efficacy of immune checkpoint inhibitors (ICIs) remains unsatisfactory in patients suffering from non-small-cell lung cancer (NSCLC). Ferroptosis, an iron-dependent cell death process, has been identified as a promising immunotherapy adjuvant; however, ferroptosis inducers (such as erastin, RSL3) may paradoxically up-regulate hypoxia-inducible factor 1α (HIF-1α) and programmed death ligand 1 (PD-L1) to propel tumor immune evasion. It is critical to explore the molecular mechanism of ferroptosis in NSCLC immunotherapy and verify the efficacy of combined regimens for overcoming ICI limitations clinically.</div></div><div><h3>Methods</h3><div>This work analyzed 162 NSCLC patients receiving immunotherapy retrospectively to evaluate correlation between PD-L1 expression and progression-free survival (PFS). In vitro, CCK-8 assay, flow cytometry, qPCR, and Western blotting were utilized to measure impacts of ferroptosis inducers (Erastin, RSL3) upon cell viability, reactive oxygen species (ROS) levels, and PD-L1/HIF-1α expression in A549/H1299 NSCLC cells; ferroptosis-specific effects were validated by means of iron chelators (DFO, ferrostatin-1). In vivo, subcutaneous tumor models were built in C57BL/6 mice with LLC cells; therapeutic effects of ferroptosis inducer (IKE) alone or combined with anti-PD-1 antibody were evaluated through tumor weight measurement and immunohistochemistry (IHC). HIF-1α binding to PD-L1 promoter was confirmed via chromatin immunoprecipitation (ChIP); related signaling pathways were explored using transcriptome sequencing and KEGG enrichment analysis.</div></div><div><h3>Results</h3><div>For NSCLC patients who received immunotherapy, high PD-L1 expression correlated with longer PFS, and 4-HNE was associated positively with PD-L1 and CD8⁺T infiltration. In vitro, Erastin/RSL3 induced dose-dependent cell death, ROS accumulation, and PD-L1 up-regulation, reversed by iron chelators. In vivo, IKE+anti-PD-1 inhibited tumor growth significantly, whereas it increased CD8⁺T infiltration. Mechanistically, Erastin up-regulated HIF-1α via PI3K-AKT, which bound PD-L1 promoter (ChIP-verified), reversed by iron chelators.</div></div><div><h3>Conclusions</h3><div>Ferroptosis inducers have dual effects in NSCLC, namely, promoting tumor cell death and triggering PD-L1-dependent immune evasion via the PI3K-AKT-HIF-1α pathway. However, combining ferroptosis inducers with anti-PD-1 antibodies retains the anti-tumor effect of ferroptosis and overcomes immune evasion by obstructing the PD-L1 pathway, offering a novel strategy for enhancing NSCLC immunotherapy efficacy.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"65 ","pages":"Article 102685"},"PeriodicalIF":5.0,"publicationDate":"2026-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146053907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-24DOI: 10.1016/j.tranon.2026.102683
Qiang Zhang , Yu Fu , Jihong Zhang
In the landscape of acute myeloid leukemia (AML) research, mutations in nucleophosmin 1 (NPM1) are the most prevalent genetic alterations. The leukemogenic mutant variant, NPM1c⁺, is associated with a distinct gene expression profile linked to leukemia, but the downstream oncogenic pathways remain only partially understood. Long non-coding RNAs (lncRNAs) are RNA molecules with known regulatory roles in human development and disease. Research implicates many lncRNAs in hematopoiesis and leukemogenesis, revealing correlations between their expression and clinical parameters in AML patients. While NPM1c⁺ AML exhibits a distinct lncRNA signature, it remains contentious whether these molecules are bona fide drivers or passenger events, and how their context-dependent functions can be therapeutically exploited.
This review focuses on lncRNAs in NPM1c⁺ AML, highlighting their roles in pathogenesis, prognosis, and chemoresistance. By systematically elucidating the role of lncRNAs as pivotal factors in the diagnosis, treatment, and prognosis of NPM1c⁺ AML, this study addresses a gap in the existing literature. Our analysis of specific lncRNAs, such as HOTAIRM1, HOXB-AS3, CRNDE, HOXBLINC, LONA, IFEX9, XLOC_109948, and HOTTIP, enhances our understanding of the molecular mechanisms underlying AML in the context of NPM1c⁺. These findings lay the groundwork for developing targeted therapies and improved prognostic tools for NPM1c⁺AML.
{"title":"NPM1c⁺-driven lncRNA dysregulation in AML: Mechanisms, Controversies and translational roadblocks","authors":"Qiang Zhang , Yu Fu , Jihong Zhang","doi":"10.1016/j.tranon.2026.102683","DOIUrl":"10.1016/j.tranon.2026.102683","url":null,"abstract":"<div><div>In the landscape of acute myeloid leukemia (AML) research, mutations in nucleophosmin 1 (<em>NPM1</em>) are the most prevalent genetic alterations. The leukemogenic mutant variant, <em>NPM1c⁺</em>, is associated with a distinct gene expression profile linked to leukemia, but the downstream oncogenic pathways remain only partially understood. Long non-coding RNAs (lncRNAs) are RNA molecules with known regulatory roles in human development and disease. Research implicates many lncRNAs in hematopoiesis and leukemogenesis, revealing correlations between their expression and clinical parameters in AML patients. While <em>NPM1c⁺</em> AML exhibits a distinct lncRNA signature, it remains contentious whether these molecules are bona fide drivers or passenger events, and how their context-dependent functions can be therapeutically exploited.</div><div>This review focuses on lncRNAs in <em>NPM1c⁺</em> AML, highlighting their roles in pathogenesis, prognosis, and chemoresistance. By systematically elucidating the role of lncRNAs as pivotal factors in the diagnosis, treatment, and prognosis of <em>NPM1c⁺</em> AML, this study addresses a gap in the existing literature. Our analysis of specific lncRNAs, such as HOTAIRM1, HOXB-AS3, CRNDE, HOXBLINC, LONA, IFEX9, XLOC_109948, and HOTTIP, enhances our understanding of the molecular mechanisms underlying AML in the context of <em>NPM1c⁺</em>. These findings lay the groundwork for developing targeted therapies and improved prognostic tools for <em>NPM1c⁺</em>AML.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"65 ","pages":"Article 102683"},"PeriodicalIF":5.0,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146047163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-24DOI: 10.1016/j.tranon.2026.102682
Yingjian Wang , Bingtong Yue , Hongqiang Ni , Jinchun Chen , Run Shi , Zhe Wang , Xinglai Dai , Maolin Sheng
Background
Clear cell renal cell carcinoma (ccRCC) frequently exhibits an immune-excluded tumor microenvironment (TME) that limits the efficacy of immune checkpoint blockade (ICB). However, the stromal–immune interactions responsible for this exclusion remain poorly understood.
Methods
We integrated eight single-cell RNA sequencing datasets, two spatial transcriptomic datasets, and bulk transcriptomic cohorts to construct a comprehensive ccRCC TME atlas. Fibroblast subsets were characterized using clustering, trajectory, transcription-factor regulon, and gene-network analyses. Stromal–immune signaling was assessed using CellChat and NicheNet, and spatial colocalization patterns were validated by SpaGene analysis. Prognostic and therapeutic relevance were evaluated in TCGA-KIRC and ICB-treated cohorts.
Results
Seven fibroblast subtypes were identified, among which periostin (POSTN)–positive cancer-associated fibroblasts (CAFs) were selectively enriched in tumors and exhibited strong activation of TGF-β, PI3K–AKT, and extracellular-matrix pathways. Trajectory and regulon inference revealed GATA6 as a key transcriptional regulator driving fibroblast differentiation toward this ECM-remodeling phenotype. Spatial analyses demonstrated that POSTN⁺ CAFs colocalized with CCL3-positive macrophages at the invasive front, forming a hypoxic, fibrotic niche that excluded CD8⁺ T cells. Ligand–receptor mapping identified reciprocal TGF-β, SPP1, and IL-6 signaling that reinforced fibro-myeloid activation. Activation of the POSTN⁺ CAF–CCL3⁺ macrophage axis correlated with poor survival and reduced response to ICB therapy.
Conclusions
This study defines a spatially organized stromal–immune signaling axis that drives immune exclusion and immunotherapy resistance in ccRCC. Targeting the POSTN⁺ CAF–CCL3⁺ macrophage interaction offers a promising strategy to remodel the fibrotic barrier and restore antitumor immunity.
透明细胞肾细胞癌（ccRCC）经常表现出免疫排斥肿瘤微环境（TME），这限制了免疫检查点阻断（ICB）的疗效。然而，导致这种排斥的基质-免疫相互作用仍然知之甚少。方法整合8个单细胞RNA测序数据集、2个空间转录组数据集和大量转录组队列，构建ccRCC TME图谱。使用聚类、轨迹、转录因子调控和基因网络分析来表征成纤维细胞亚群。使用CellChat和NicheNet评估基质免疫信号，并通过SpaGene分析验证空间共定位模式。在TCGA-KIRC和icb治疗组中评估预后和治疗相关性。结果鉴定出7种成纤维细胞亚型，其中骨膜蛋白（POSTN）阳性的癌相关成纤维细胞（CAFs）在肿瘤中选择性富集，并表现出TGF-β、PI3K-AKT和细胞外基质通路的强激活。轨迹和调控推断显示GATA6是驱动成纤维细胞向这种ecm重塑表型分化的关键转录调节因子。空间分析表明，POSTN + CAFs与侵袭前沿的ccl3阳性巨噬细胞共定位，形成一个缺氧的纤维化生态位，排除了CD8 + T细胞。配体受体定位鉴定了相互的TGF-β、SPP1和IL-6信号，增强了纤维髓细胞的激活。POSTN + ca - ccl3 +巨噬细胞轴的激活与较差的生存率和对ICB治疗的反应降低相关。结论本研究确定了ccRCC中驱动免疫排斥和免疫治疗耐药的空间组织基质免疫信号轴。针对POSTN + ca - ccl3 +巨噬细胞的相互作用，为重塑纤维化屏障和恢复抗肿瘤免疫提供了一种有希望的策略。
{"title":"POSTN⁺ cancer-associated fibroblast–CCL3⁺ macrophage crosstalk defines the immune-excluded tumor microenvironment in clear cell renal cell carcinoma","authors":"Yingjian Wang , Bingtong Yue , Hongqiang Ni , Jinchun Chen , Run Shi , Zhe Wang , Xinglai Dai , Maolin Sheng","doi":"10.1016/j.tranon.2026.102682","DOIUrl":"10.1016/j.tranon.2026.102682","url":null,"abstract":"<div><h3>Background</h3><div>Clear cell renal cell carcinoma (ccRCC) frequently exhibits an immune-excluded tumor microenvironment (TME) that limits the efficacy of immune checkpoint blockade (ICB). However, the stromal–immune interactions responsible for this exclusion remain poorly understood.</div></div><div><h3>Methods</h3><div>We integrated eight single-cell RNA sequencing datasets, two spatial transcriptomic datasets, and bulk transcriptomic cohorts to construct a comprehensive ccRCC TME atlas. Fibroblast subsets were characterized using clustering, trajectory, transcription-factor regulon, and gene-network analyses. Stromal–immune signaling was assessed using CellChat and NicheNet, and spatial colocalization patterns were validated by SpaGene analysis. Prognostic and therapeutic relevance were evaluated in TCGA-KIRC and ICB-treated cohorts.</div></div><div><h3>Results</h3><div>Seven fibroblast subtypes were identified, among which periostin (POSTN)–positive cancer-associated fibroblasts (CAFs) were selectively enriched in tumors and exhibited strong activation of TGF-β, PI3K–AKT, and extracellular-matrix pathways. Trajectory and regulon inference revealed GATA6 as a key transcriptional regulator driving fibroblast differentiation toward this ECM-remodeling phenotype. Spatial analyses demonstrated that POSTN⁺ CAFs colocalized with CCL3-positive macrophages at the invasive front, forming a hypoxic, fibrotic niche that excluded CD8⁺ T cells. Ligand–receptor mapping identified reciprocal TGF-β, SPP1, and IL-6 signaling that reinforced fibro-myeloid activation. Activation of the POSTN⁺ CAF–CCL3⁺ macrophage axis correlated with poor survival and reduced response to ICB therapy.</div></div><div><h3>Conclusions</h3><div>This study defines a spatially organized stromal–immune signaling axis that drives immune exclusion and immunotherapy resistance in ccRCC. Targeting the POSTN⁺ CAF–CCL3⁺ macrophage interaction offers a promising strategy to remodel the fibrotic barrier and restore antitumor immunity.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"65 ","pages":"Article 102682"},"PeriodicalIF":5.0,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146039060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-24DOI: 10.1016/j.tranon.2026.102684
Yi Du , Quan Yuan , Hao Yu , Rongjie Ye , Huan Lin , Ge Yu , Ming Niu , Huilei Qiu
Background
Breast cancer (BC) is the most common malignancy afflicting women worldwide, yet the role of relaxin-related genes (RLN) in BC progression remains unclear. This study aims to elucidate the relationship between RLN and BC outcomes through immune microenvironment and metabolic pathway analysis.
Methods
Gene expression and clinical data were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Relaxin-related genes were identified using KEGG and Genecard databases. A prognostic model, the RLN Associated Prognostic Model (TRAPM), was established using 101 combinations of 10 machine learning algorithms and validated at the single-cell level. Multi-omics analysis, including the IMvigor210 cohort, was performed to assess TRAPM’s applicability in immunotherapy and drug selection.
Results
TRAPM, comprising nine prognostic genes (MMP1, RXFP1, PRKCZ, JUN, NFKBIA, GNAI2, NOS2, MMP9, and MMP13), showed significant associations with immune and metabolic profiles. Using TRAPM, a novel BC subtype RC3 and its key marker genes (MTHFD1L, CAVIN4, MMP1, ADGRG6, B3GNT5, SMYD2, and TFRC) were identified. Experimental validation through RT-qPCR and Western Blot confirmed the role of these markers in six BRCA cell lines.
Conclusions
The identification of TRAPM and the RC3 subtype enhances our understanding of BC heterogeneity and highlights potential therapeutic targets. This study provides a foundation for personalized treatment strategies by clarifying the biological significance and clinical relevance of the RC3 subtype.
{"title":"Utilization of machine learning algorithms for the identification of the RLN associated prognostic model and feature biomarkers of RLN-related subtypes in breast cancer","authors":"Yi Du , Quan Yuan , Hao Yu , Rongjie Ye , Huan Lin , Ge Yu , Ming Niu , Huilei Qiu","doi":"10.1016/j.tranon.2026.102684","DOIUrl":"10.1016/j.tranon.2026.102684","url":null,"abstract":"<div><h3>Background</h3><div>Breast cancer (BC) is the most common malignancy afflicting women worldwide, yet the role of relaxin-related genes (RLN) in BC progression remains unclear. This study aims to elucidate the relationship between RLN and BC outcomes through immune microenvironment and metabolic pathway analysis.</div></div><div><h3>Methods</h3><div>Gene expression and clinical data were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Relaxin-related genes were identified using KEGG and Genecard databases. A prognostic model, the RLN Associated Prognostic Model (TRAPM), was established using 101 combinations of 10 machine learning algorithms and validated at the single-cell level. Multi-omics analysis, including the IMvigor210 cohort, was performed to assess TRAPM’s applicability in immunotherapy and drug selection.</div></div><div><h3>Results</h3><div>TRAPM, comprising nine prognostic genes (MMP1, RXFP1, PRKCZ, JUN, NFKBIA, GNAI2, NOS2, MMP9, and MMP13), showed significant associations with immune and metabolic profiles. Using TRAPM, a novel BC subtype RC3 and its key marker genes (MTHFD1L, CAVIN4, MMP1, ADGRG6, B3GNT5, SMYD2, and TFRC) were identified. Experimental validation through RT-qPCR and Western Blot confirmed the role of these markers in six BRCA cell lines.</div></div><div><h3>Conclusions</h3><div>The identification of TRAPM and the RC3 subtype enhances our understanding of BC heterogeneity and highlights potential therapeutic targets. This study provides a foundation for personalized treatment strategies by clarifying the biological significance and clinical relevance of the RC3 subtype.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"65 ","pages":"Article 102684"},"PeriodicalIF":5.0,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146039061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-23DOI: 10.1016/j.tranon.2026.102665
Rongjiang Wang , Mengting Jiang , Zhaojun Li , Zhucheng Zhao , Junwen Shen
Objective
Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment and play a significant role in renal cell carcinoma (RCC) progression and treatment response. However, current methods for evaluating CAFs infiltration in RCC are inadequate. This study aims to develop a non-invasive histopathological model based on H&E staining and collagen features to predict CAFs infiltration and investigate its prognostic value and biological relevance.
Methods
We conducted a retrospective analysis using H&E pathological images and clinical data from The Cancer Genome Atlas (TCGA) database. A Pathomics model integrating 465 histopathological features was constructed using machine learning algorithms (n = 354) to predict CAFs infiltration. A preliminary technical validation was performed using multiphoton microscopy-based collagen quantification (n = 25) to assess the correlation between the Pathomics Score and CAF-related fibrotic activity. Enrichment analysis, immune cell infiltration profiling, and mutation analysis were employed to explore the biological mechanisms underlying the model.
Results
The Pathomics model demonstrated high predictive accuracy (AUC=0.813) and correlated significantly with collagen deposition (r = 0.66, P < 0.001). High Pathomics scores were independently associated with poor survival (HR=1.80, P = 0.003) and linked to key biological processes, including YAP/TAZ activation, extracellular matrix (ECM) remodeling, immune suppression (e.g., CD276, IDO1), and frequent mutations in VHL and PBRM1 (>40%).
Conclusion
This study establishes the first H&E-based Pathomics framework for quantifying CAFs infiltration in RCC, providing a cost-effective and non-invasive tool for preliminary risk stratification. The model’s strong correlation with collagen features and its ability to reveal underlying molecular mechanisms highlight its potential for potential value in understanding the stromal microenvironment, though further external validation is required for clinical translation.
癌症相关成纤维细胞（CAFs）是肿瘤微环境的重要组成部分，在肾细胞癌（RCC）的进展和治疗反应中起着重要作用。然而，目前评估CAFs在碾压细胞浸润的方法是不充分的。本研究旨在建立一种基于H&；E染色和胶原蛋白特征的无创组织病理学模型来预测CAFs浸润，并探讨其预后价值和生物学相关性。方法回顾性分析来自美国癌症基因组图谱（TCGA）数据库的H&；E病理图像和临床资料。利用机器学习算法（n = 354）构建了一个包含465个组织病理学特征的病理模型来预测CAFs的浸润。采用基于多光子显微镜的胶原定量（n = 25）进行了初步技术验证，以评估病理评分与ca相关纤维化活性之间的相关性。利用富集分析、免疫细胞浸润分析和突变分析来探索该模型背后的生物学机制。结果病理学模型预测准确率高（AUC=0.813），与胶原沉积有显著相关性（r = 0.66, P < 0.001）。高病理评分与较差的生存率独立相关（HR=1.80, P = 0.003），并与关键的生物学过程相关，包括YAP/TAZ激活、细胞外基质（ECM）重塑、免疫抑制（如CD276、IDO1）以及VHL和PBRM1的频繁突变（>40%）。本研究建立了第一个基于H&的病理框架，用于量化肾癌中CAFs的浸润，为初步风险分层提供了一种经济、无创的工具。该模型与胶原蛋白特征的强相关性及其揭示潜在分子机制的能力突出了其在理解基质微环境方面的潜在价值，尽管临床转化需要进一步的外部验证。
{"title":"An exploratory study on the relationship between renal cell carcinoma and CAFs infiltration by integrating Pathomics and collagen features","authors":"Rongjiang Wang , Mengting Jiang , Zhaojun Li , Zhucheng Zhao , Junwen Shen","doi":"10.1016/j.tranon.2026.102665","DOIUrl":"10.1016/j.tranon.2026.102665","url":null,"abstract":"<div><h3>Objective</h3><div>Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment and play a significant role in renal cell carcinoma (RCC) progression and treatment response. However, current methods for evaluating CAFs infiltration in RCC are inadequate. This study aims to develop a non-invasive histopathological model based on H&E staining and collagen features to predict CAFs infiltration and investigate its prognostic value and biological relevance.</div></div><div><h3>Methods</h3><div>We conducted a retrospective analysis using H&E pathological images and clinical data from The Cancer Genome Atlas (TCGA) database. A Pathomics model integrating 465 histopathological features was constructed using machine learning algorithms (<em>n</em> = 354) to predict CAFs infiltration. A preliminary technical validation was performed using multiphoton microscopy-based collagen quantification (<em>n</em> = 25) to assess the correlation between the Pathomics Score and CAF-related fibrotic activity. Enrichment analysis, immune cell infiltration profiling, and mutation analysis were employed to explore the biological mechanisms underlying the model.</div></div><div><h3>Results</h3><div>The Pathomics model demonstrated high predictive accuracy (AUC=0.813) and correlated significantly with collagen deposition (<em>r</em> = 0.66, <em>P</em> < 0.001). High Pathomics scores were independently associated with poor survival (HR=1.80, <em>P</em> = 0.003) and linked to key biological processes, including YAP/TAZ activation, extracellular matrix (ECM) remodeling, immune suppression (e.g., CD276, IDO1), and frequent mutations in VHL and PBRM1 (>40%).</div></div><div><h3>Conclusion</h3><div>This study establishes the first H&E-based Pathomics framework for quantifying CAFs infiltration in RCC, providing a cost-effective and non-invasive tool for preliminary risk stratification. The model’s strong correlation with collagen features and its ability to reveal underlying molecular mechanisms highlight its potential for potential value in understanding the stromal microenvironment, though further external validation is required for clinical translation.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"65 ","pages":"Article 102665"},"PeriodicalIF":5.0,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146039085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-22DOI: 10.1016/j.tranon.2026.102678
Wencong Ma , Cheng Zhang , Anjiang Gou , Mingtai Hu, Yao Huang, Xiaoqing Jiang, Jianyang Ao, Jinghan Wang
Gallbladder cancer (GBC) is a highly aggressive malignancy of the biliary tract with limited therapeutic options. Phosphoglucomutase 5 (PGM5), a key enzyme in glucose metabolism, has been implicated as a tumor suppressor in several cancers, yet its role and mechanism in GBC remain unclear. Here, we demonstrate that PGM5 is significantly downregulated in GBC tissues, and its low expression correlates with poor prognosis. Using integrated bioinformatic analysis, we found that PGM5 loss is associated with enhanced glycolysis and activation of the STAT3 signaling pathway. Functionally, PGM5 overexpression significantly inhibited GBC cell proliferation, migration, and invasion, and promoted apoptosis, whereas PGM5 knockdown exerted the opposite effects. Mechanistically, PGM5 suppressed lactate production by downregulating lactate dehydrogenase A (LDHA), leading to decreased phosphorylation of STAT3. The anti-tumor effects of PGM5 were reversed by exogenous lactate supplementation, and the glycolytic inhibitor 2-DG abrogated the oncogenic phenotypes induced by PGM5 silencing. In a mouse xenograft model, PGM5 overexpression significantly restrained tumor growth, reduced LDHA and p-STAT3 levels, and decreased intratumoral lactate content. Our findings reveal that PGM5 acts as a tumor suppressor in GBC through disruption of the lactate-STAT3 signaling axis, highlighting its potential as a therapeutic target for metabolic intervention in GBC.
{"title":"Phosphoglucomutase 5 suppresses gallbladder cancer progression by inhibiting lactate-driven STAT3 signaling","authors":"Wencong Ma , Cheng Zhang , Anjiang Gou , Mingtai Hu, Yao Huang, Xiaoqing Jiang, Jianyang Ao, Jinghan Wang","doi":"10.1016/j.tranon.2026.102678","DOIUrl":"10.1016/j.tranon.2026.102678","url":null,"abstract":"<div><div>Gallbladder cancer (GBC) is a highly aggressive malignancy of the biliary tract with limited therapeutic options. Phosphoglucomutase 5 (PGM5), a key enzyme in glucose metabolism, has been implicated as a tumor suppressor in several cancers, yet its role and mechanism in GBC remain unclear. Here, we demonstrate that PGM5 is significantly downregulated in GBC tissues, and its low expression correlates with poor prognosis. Using integrated bioinformatic analysis, we found that PGM5 loss is associated with enhanced glycolysis and activation of the STAT3 signaling pathway. Functionally, PGM5 overexpression significantly inhibited GBC cell proliferation, migration, and invasion, and promoted apoptosis, whereas PGM5 knockdown exerted the opposite effects. Mechanistically, PGM5 suppressed lactate production by downregulating lactate dehydrogenase A (LDHA), leading to decreased phosphorylation of STAT3. The anti-tumor effects of PGM5 were reversed by exogenous lactate supplementation, and the glycolytic inhibitor 2-DG abrogated the oncogenic phenotypes induced by PGM5 silencing. In a mouse xenograft model, PGM5 overexpression significantly restrained tumor growth, reduced LDHA and p-STAT3 levels, and decreased intratumoral lactate content. Our findings reveal that PGM5 acts as a tumor suppressor in GBC through disruption of the lactate-STAT3 signaling axis, highlighting its potential as a therapeutic target for metabolic intervention in GBC.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"65 ","pages":"Article 102678"},"PeriodicalIF":5.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146039084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-21DOI: 10.1016/j.tranon.2026.102681
Quan Liu , Maoxin Ran , Wenying Shan , Shao-Lin Zhang , Kin Yip Tam
Targeting Pyruvate dehydrogenase kinase (PDK) has emerged as one of the potential therapeutic strategies for non-small cell lung carcinoma (NSCLC). 64, a recently reported PDK1 inhibitor derived from 2,2-dichloroacetophenone (DAP), exhibited promising anticancer effects in NSCLC models. Herein, we sought to investigate the mechanism of action of 64 in two NSCLC cell lines, namely, NCI-H1975 and NCI-H1650. We found that 64 induced intrinsic cancer cell apoptosis by releasing cytochrome C (CytC) from mitochondria, leading to caspase-3 and poly (ADP-ribose) polymerase (PARP) cleavage, which was mediated by reactive oxygen species (ROS). Moreover, we have shown that 64 induced mitochondrial membrane potential (MMP) depolarization and AMPK/MAPK activations were also ROS driven. With the aid of sequencing studies and follow-up biochemical evaluations, we found that 64 activated the NF-κB pathway through P38 MAPK, while the combination of P38 MAPK inhibitor SB203580 with 64 diminished such activation. Interestingly, the combined use of 64 and NF-κB inhibitor (JSH-23) increased pro-apoptosis protein (Bax) expression and decreased pro-survival protein (Bcl-2) expression, resulting in enhanced cancer cell apoptosis via JNK pathway. Our results suggested that 64 induces cancer cell apoptosis in NSCLC models through ROS, while NF-κB activation serves as a survival mechanism upon PDK1 inhibition.
{"title":"NF-κB activation as a pro-survival signal from pharmacological inhibition of pyruvate dehydrogenase kinase 1 in non-small-cell lung carcinoma cell models","authors":"Quan Liu , Maoxin Ran , Wenying Shan , Shao-Lin Zhang , Kin Yip Tam","doi":"10.1016/j.tranon.2026.102681","DOIUrl":"10.1016/j.tranon.2026.102681","url":null,"abstract":"<div><div>Targeting Pyruvate dehydrogenase kinase (PDK) has emerged as one of the potential therapeutic strategies for non-small cell lung carcinoma (NSCLC). <strong>64</strong>, a recently reported PDK1 inhibitor derived from 2,2-dichloroacetophenone (DAP), exhibited promising anticancer effects in NSCLC models. Herein, we sought to investigate the mechanism of action of <strong>64</strong> in two NSCLC cell lines, namely, NCI-H1975 and NCI-H1650. We found that <strong>64</strong> induced intrinsic cancer cell apoptosis by releasing cytochrome C (CytC) from mitochondria, leading to caspase-3 and poly (ADP-ribose) polymerase (PARP) cleavage, which was mediated by reactive oxygen species (ROS). Moreover, we have shown that <strong>64</strong> induced mitochondrial membrane potential (MMP) depolarization and AMPK/MAPK activations were also ROS driven. With the aid of sequencing studies and follow-up biochemical evaluations, we found that <strong>64</strong> activated the NF-κB pathway through P38 MAPK, while the combination of P38 MAPK inhibitor <strong>SB203580</strong> with <strong>64</strong> diminished such activation. Interestingly, the combined use of <strong>64</strong> and NF-κB inhibitor (<strong>JSH-23</strong>) increased pro-apoptosis protein (Bax) expression and decreased pro-survival protein (Bcl-2) expression, resulting in enhanced cancer cell apoptosis <em>via</em> JNK pathway. Our results suggested that <strong>64</strong> induces cancer cell apoptosis in NSCLC models through ROS, while NF-κB activation serves as a survival mechanism upon PDK1 inhibition.</div></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":"65 ","pages":"Article 102681"},"PeriodicalIF":5.0,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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