Clinical & Translational Oncology[JOURNAL]
Sun
200 papers
Loss of the RAGE function in hypoxic conditions exacerbates the malignant progression of lung adenocarcinoma via damage-associated molecular pattern signaling.
Xiao H, Song X, Wuren T … +1 more , Ge RL
Transl Oncol · 2026 Jun · PMID 42314516 · Full text
Despite therapeutic advances, lung adenocarcinoma (LUAD) remains difficult to treat, and the mechanisms by which hypoxia promotes tumor progression are still incompletely understood. Because the receptor for advanced gly...
Despite therapeutic advances, lung adenocarcinoma (LUAD) remains difficult to treat, and the mechanisms by which hypoxia promotes tumor progression are still incompletely understood. Because the receptor for advanced glycation end products (RAGE) has been implicated in hypoxia-related signaling, we investigated the interaction between damage-associated molecular patterns (DAMPs) and RAGE in LUAD under hypoxic conditions using the RAGE inhibitor FPS-ZM1 in vitro and in vivo. RAGE expression was significantly reduced in LUAD samples and was associated with poor survival. LUAD tissues also showed evidence of hypoxia, including elevated hypoxia-inducible factor-1α (HIF-1α). Under hypoxia, S100A8/A9 redistributed from the nucleus to the cytoplasm, whereas intracellular HMGB1 levels decreased. In vitro, FPS-ZM1 suppressed NF-κB phosphorylation and inhibited LLC cell viability and migration. In contrast, in vivo FPS-ZM1 treatment was associated with enhanced tumor progression, increased HIF-1α and S100A8/A9 expression, and reactivation of NF-κB signaling. These findings suggest that RAGE blockade may trigger context-dependent compensatory responses within the tumor microenvironment. We therefore present a working model in which a hypoxia-associated HIF-1α/S100A8/A9 axis may bypass RAGE inhibition and restore pro-tumor signaling; however, this mechanism requires direct experimental validation. Overall, our data highlight the importance of tumor-microenvironment context when interpreting RAGE-targeted interventions in LUAD.
GPR107-EGFR crosstalk promotes ovarian cancer metastasis by regulating IL-6 release via PI3K/AKT/NF-κB signaling pathway.
Zhao J, Wang X, Li T … +4 more , Chen J, Zhu H, Yang L, Liang Y
Transl Oncol · 2026 Jun · PMID 42314515 · Full text
Ovarian cancer (OVCA) has the highest mortality rate among all gynecological malignancies. Epidermal growth factor receptor (EGFR) is commonly overexpressed in epithelial OVCA (30-98%) and is significantly positively cor...
Ovarian cancer (OVCA) has the highest mortality rate among all gynecological malignancies. Epidermal growth factor receptor (EGFR) is commonly overexpressed in epithelial OVCA (30-98%) and is significantly positively correlated with poor patient prognosis. However, therapeutic drugs targeting EGFR have not shown promising results, indicating the existence of other potential mechanisms. G-protein-coupled receptor (GPCR) families were reported to crosstalk with EGFR, jointly affecting the activation of downstream signaling pathway networks. G protein-coupled receptor 107 (GPR107), a novel orphan GPCR, is overexpressed in tumors and is involved in cancer progression. Little is known about the role of GPR107 in OVCA progression. In this study, the underlying mechanism of GPR107-EGFR crosstalk and its critical function in OVCA progression were investigated. GPR107, which was highly expressed in OVCA and was associated with advanced clinical stages, could interact with EGFR on the cell membrane and promoted the invasion, migration, and epithelial mesenchymal transition (EMT) of OVCA. Mechanistically, GPR107-EGFR crosstalk promoted EGFR phosphorylation and downstream PI3K/AKT/NF-κB activation, resulting in autocrine IL-6 secretion, which facilitated OVCA metastasis both in vitro and in vivo. Monoclonal antibodies targeting IL-6 could inhibit OVCA metastasis induced by GPR107. In conclusion, our study highlights the importance of GPR107-EGFR crosstalk in OVCA metastasis by clarifying the function and molecular mechanism of GPR107-EGFR crosstalk, and provides a novel direction for developing new treatment strategies for OVCA.
Combined inhibition of CDK4/6 and PI3K pathways exhibit highly synergistic activity and translational potential in Ewing sarcoma.
Gloege HF, De Los Santos MAIC, Chakraborty A … +15 more , Chadha M, Aguilar-Quintero A, Shen M, Heaslip CO, Finstuen-Magro S, McDannell B, Tanhaemami M, Meyer S, Klega K, Zhang YQ, Shulman DS, DuBois SG, Hall MD, Blandin AF, Crompton BD
Transl Oncol · 2026 Jun · PMID 42314514 · Full text
Ewing sarcoma is a highly aggressive solid malignancy affecting children and young adults. Ewing sarcoma is driven primarily by EWSR1::FLI1, a fusion oncoprotein that has been notoriously difficult to target with traditi...
Ewing sarcoma is a highly aggressive solid malignancy affecting children and young adults. Ewing sarcoma is driven primarily by EWSR1::FLI1, a fusion oncoprotein that has been notoriously difficult to target with traditional pharmacologic agents. There are numerous examples of promising preclinical combinations of small molecules that are never tested in pediatric clinical trials because agents fail to reach the market due to limited efficacy for common adult cancers. Moreover, the effectiveness of single-agent therapies for cancer treatment is often limited. To address these limitations, we selected 28 compounds that were FDA approved at the time of the study or in late stages of clinical development and known to regulate important pathways in Ewing sarcoma. We performed a drug screen in Ewing sarcoma cell lines with 180 combinations of tyrosine kinase inhibitors, cell cycle inhibitors, and conventional chemotherapy. The results of the screen revealed that a PI3K inhibitor, copanlisib, combined with a CDK4/6 inhibitor, ribociclib, exhibited strong synergistic anti-Ewing sarcoma activity. Using proteomic methods such as a reverse-phase protein array and western immunoblotting, we demonstrated that this combination induced a downregulation of the PI3K/AKT pathway as well as proteins involved in cell cycle regulation. We further confirmed these in vitro data using bulk RNA-sequencing. To evaluate the phenotypic effect of the PI3K/CDK4/6 inhibition in Ewing sarcoma lines, we performed apoptosis and cell cycle analyses using flow cytometry and demonstrated that ribociclib primarily induced a G0/G1 arrest with minimal effect on Ewing cell viability but significantly enhanced the apoptotic effect of copanlisib treatment. In two xenograft models of Ewing sarcoma, we demonstrated that the combination significantly prolonged survival compared to treatment with either vehicle or single-agent therapy alone. Our findings identify a new candidate therapy combination for Ewing sarcoma and provide a resource of additional potential synergistic combinations for future validation.
Multi-omics identifies VMP1 as a tumor-intrinsic biomarker associated with metastatic progression and immune microenvironment remodeling in HNSCC.
Li X, Yang A, Yue L … +2 more , Jing C, Wang X
Transl Oncol · 2026 Jun · PMID 42314513 · Full text
Head and neck squamous cell carcinoma (HNSCC) frequently exhibits metastatic progression and develops an immunosuppressive microenvironment. However, the tumor cell-intrinsic factors contributing to metastasis-associated...
Head and neck squamous cell carcinoma (HNSCC) frequently exhibits metastatic progression and develops an immunosuppressive microenvironment. However, the tumor cell-intrinsic factors contributing to metastasis-associated immune remodeling remain incompletely understood. Here, we integrated two independent single-cell RNA-seq cohorts (GSE243933 and GSE181919) to compare primary and metastatic HNSCC ecosystems and identified vacuole membrane protein 1 (VMP1) as a malignant cell-intrinsic gene consistently upregulated across metastatic contexts. In TCGA-HNSCC and two GEO cohorts (GSE65858 and GSE117973), high VMP1 expression was associated with poor prognosis and enrichment of invasion-related programs, including epithelial-mesenchymal transition (EMT) and TNFα/NF-κB signaling, and was also associated with decreased CD8⁺ T-cell infiltration and impaired effector features. In an independent HNSCC tissue cohort, immunohistochemistry confirmed elevated VMP1 protein expression in tumors and its association with advanced clinicopathological features and unfavorable survival. Functionally, gain- and loss-of-function experiments in SCC25 and CAL27 cells showed that VMP1 enhances proliferation, migration, and invasion, accompanied by EMT-like marker switching, increased RelA/p65 phosphorylation, and elevated PD-L1 expression. Collectively, VMP1 identifies a metastasis-associated tumor-intrinsic factor associated with invasive progression and reduced CD8⁺ T-cell activity. The concomitant NF-κB activation and PD-L1 induction support a potential VMP1-associated NF-κB/PD-L1 link that may contribute to the association between invasion-related programs and immune modulation. These findings support the potential biomarker relevance of VMP1 and provide a rationale for further mechanistic and clinical investigation in HNSCC.
Corrigendum to "The role of A-kinase interacting protein 1 in regulating progression and stemness as well as indicating the prognosis in glioblastoma" [Translational Oncology 22 (2022) 101463].
Tang J, Peng S, Yan H … +4 more , Ni M, Hou X, Ma P, Li Y
Transl Oncol · 2026 Aug · PMID 42309617 · Full text
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The tumor-microenvironment-associated prognostic gene TIGIT promotes malignant phenotypes in esophageal carcinoma.
Wang W, Ye L, Sheng J … +5 more , Wen L, Li H, Hong W, Ji Y, Xu X
Transl Oncol · 2026 Jun · PMID 42302480 · Full text
BACKGROUND: Previous studies have shown that tumor immune microenvironment related markers are associated with tumor prognosis. However, few studies have explored the prognostic value of tumor cell surface biomarkers (e....
BACKGROUND: Previous studies have shown that tumor immune microenvironment related markers are associated with tumor prognosis. However, few studies have explored the prognostic value of tumor cell surface biomarkers (e.g., CD8, TIM3, PD-L1, LAG3, CD163, and TIGIT) in resectable ESCC. METHODS: We retrospectively analyzed 69 ESCC patients who underwent complete resection at Zhejiang Cancer Hospital. Using multiplex immunofluorescence histochemistry, we evaluated the expression of CD8, TIM3, PD-L1, LAG3, CD163, and TIGIT in tumor and immune microenvironments and their associations with clinical outcomes. Triple-color immunofluorescence confirmed TIGIT expression in ESCC tissues. Functional roles of TIGIT were further investigated via RNA-seq, real-time PCR, WB, CCK-8 assays, transwell assays, and flow cytometry. RESULTS: The median follow-up was 47.7 months. High expression was most frequent for CD8 (52.2%), followed by TIM3 (29.0%), PD-L1 (17.4%), LAG3 (24.6%), TIGIT (20.3%), and CD163 (14.5%). Median DFS was 17.4 months and OS was 26.8 months. Higher TIGIT expression correlated with shorter DFS and OS. Stratification by TIGIT-to-PAN-CK ratio confirmed that higher tumor-cell TIGIT was an unfavorable prognostic indicator. Functional analyses showed that TIGIT knockdown reduced ESCC cell migration, invasion, and proliferation, and altered cell cycle distribution with S-phase accumulation. RNA-sequencing implicated cytokine-receptor interactions and the JAK-STAT signaling axis in TIGIT-mediated functions. CONCLUSIONS: TIGIT, along with PD-L1 and CD163, is a potential prognostic marker for resectable ESCC. TIGIT is not only expressed in immune cells but also in ESCC tumor cells, suggesting its potential as a biomarker and therapeutic target. Further mechanistic studies are warranted to elucidate the downstream signaling pathways and validate the mechanisms of TIGIT in ESCC.
Circ_0008777 promotes head and neck squamous cell carcinoma progression by elevating c-Myc expression levels via interacting with PC4 and miR-185-3p.
Liu W, Wang Z, Li P … +5 more , Liu Y, Chen J, Shi Z, Liu H, Ye J
Transl Oncol · 2026 Jun · PMID 42302478 · Full text
Circular RNAs (circRNAs) have emerged as key players in tumor progression, yet their role in head and neck squamous cell carcinoma (HNSCC) remains largely unexplored. The AURKA gene is frequently amplified and activated...
Circular RNAs (circRNAs) have emerged as key players in tumor progression, yet their role in head and neck squamous cell carcinoma (HNSCC) remains largely unexplored. The AURKA gene is frequently amplified and activated in HNSCC. This study investigates the expression patterns and functions of circ_0008777, which is derived from AURKA exons 3-6, in HNSCC. The biological functions of circ_0008777 were evaluated in vitro and in vivo, along with its interactions with positive cofactor 4 (PC4) and miR-185-3p. Our data indicated that circ_0008777 expression levels are upregulated in HNSCC tissues and cell lines, and linked to aggressive clinical features. Knocking down circ_0008777 significantly inhibited HNSCC cell proliferation and migration in vitro, as well as restrained tumor growth in vivo, while overexpressing circ_0008777 had the opposite effects. Mechanistically, circ_0008777 can bind to PC4 to increase c-Myc transcription. Bioinformatics analysis showed that PC4 is highly expressed in HNSCC patients, with survival analysis revealing a negative correlation between PC4 expression and overall survival rates. PC4 knockout could hinder HNSCC cell proliferation and migration in vitro. Additionally, circ_0008777 can bind to miR-185-3p through a microRNA sponge mechanism, relieving miR-185-3p-mediated repression of c-Myc mRNA. Furthermore, the inhibitory effects of circ_0008777 knockdown on the cell migration and proliferation rates were rescued by c-Myc overexpression. In conclusion, circ_0008777 can promote HNSCC progression by upregulating c-Myc expression through both PC4- and miR-185-3p-related mechanisms, showing potential as a candidate therapeutic target in this cancer.
Real-world evidence of RET fusion prevalence and testing in patients with metastatic non-small cell lung cancer.
Garcia BNC, de Jager VD, Epskamp-Kuijpers CCHJ … +4 more , van der Wekken AJ, Willems SM, van Kempen LC, Schuuring E
Transl Oncol · 2026 Aug · PMID 42288045 · Full text
OBJECTIVES: Rearranged during transfection (RET) fusion is a driver aberration in non-small cell lung cancer (NSCLC). Approval of RET inhibitors selpercatinib and pralsetinib prompts adequate molecular testing for RET fu...
OBJECTIVES: Rearranged during transfection (RET) fusion is a driver aberration in non-small cell lung cancer (NSCLC). Approval of RET inhibitors selpercatinib and pralsetinib prompts adequate molecular testing for RET fusions in NSCLC. The aim of this study was to determine changes in the detection of RET fusions and the effect of various testing strategies in stage IV NSCLC patients using real-world data. MATERIALS AND METHODS: Patients diagnosed with metastatic non-squamous NSCLC in 2017 and 2019 were selected from Netherlands Cancer Registry (NCR) database and linked to their pathology reports form the Dutch nationwide pathology databank (Palga). Based on these data, RET fusion testing rates, prevalence and laboratory variation were evaluated. RESULTS: A total of 3651 patients and 3934 patients were included in 2017 and 2019, respectively. The prevalence of RET fusion in non-squamous NSCLC was 1.3% and 0.7%, in 2017 and 2019, respectively. The overall RET fusion testing rate increased from 22.6% (2017) to 31.8% (2019). Between 2017 and 2019, a shift from FISH (91% to 47%) to RNA-based testing (6% to 46%) for the detection of RET fusions was observed. CONCLUSION: The prevalence calculated from real-world data in the Netherlands with nation-wide coverage was 1.3% in 2017 and 0.7% in 2019. The decrease in detected RET fusions between 2017 and 2019 was associated with decreased use of FISH testing The prevalence of RET fusions in non-squamous NSCLC published in the literature (1-2%) is therefore likely overestimated.
High SOX17 expression is correlated with favorable prognosis and CD8(+) TILs expression in patients with pancreatic cancer after curative resection.
Yu J, Pan Y, Chen Y … +6 more , Shu Z, Ma L, Wu B, Li J, Li J, Lan C
Transl Oncol · 2026 Aug · PMID 42288044 · Full text
OBJECTIVE: The SRY-box transcription factor 17 (SOX17) plays a critical role in tumorigenesis and tumor progression and reshaping the tumor immune ecosystem in several cancer types, but its role in pancreatic cancer (PC)...
OBJECTIVE: The SRY-box transcription factor 17 (SOX17) plays a critical role in tumorigenesis and tumor progression and reshaping the tumor immune ecosystem in several cancer types, but its role in pancreatic cancer (PC) remains unknown. METHODS: A total of 168 patients with PC who underwent curative resection were consecutively enrolled, and immunohistochemical (IHC) staining was performed, followed by Kaplan-Meier and Cox proportional hazards regression analyses. Meanwhile, specific markers of cancer-associated fibroblasts (CAFs) and tumor-infiltrating lymphocytes (TILs) and PD-L1 expression were detected by IHC staining, and their correlation with SOX17 were evaluated. Finally, single-cell and bulk RNA-seq analyses of public datasets were used to validate the expression profile of SOX17 in PC. RESULTS: The Kaplan-Meier curve showed that high SOX17 expression was correlated with a longer overall survival (OS) and disease-free survival (DFS) in patients with PC. Univariate (hazard ratio [HR] = 0.593, P = 0.005 for OS; HR = 0.602, P = 0.012 for DFS) and multivariate (HR = 0.662, P = 0.042 for OS; HR = 0.602, P = 0.036 for DFS) Cox regression analyses demonstrated that high SOX17 expression was an independent favorable prognostic factor. The correlation analysis showed that SOX17 expression was correlated with the expression of CD8+ TILs (P = 0.012) and FAP+ CAFs (P = 0.011). The correlations between SOX17 and CD8+ TILs were validated by multiple algorithms through single-cell and bulk RNA-seq analyses. CONCLUSION: The present study demonstrates that SOX17 serves as a significant prognostic marker and reflects the tumor immune ecosystem in pancreatic cancer.
HIF1-driven TDP-43 stabilizes TRIP6 mRNA to drive angiogenesis and colorectal cancer progression under hypoxia.
Cheng K, Liu Y, Feng W … +2 more , Xu D, Hao B
Transl Oncol · 2026 Aug · PMID 42284709 · Full text
Hypoxia is a key feature of the tumor microenvironment in colorectal cancer (CRC), but the mechanisms linking hypoxia to metastasis remain incompletely understood. To investigate this, bioinformatics analysis of The Canc...
Hypoxia is a key feature of the tumor microenvironment in colorectal cancer (CRC), but the mechanisms linking hypoxia to metastasis remain incompletely understood. To investigate this, bioinformatics analysis of The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) datasets assessed TAR DNA-binding protein 43 (TDP-43) expression and its correlation with hypoxia-inducible factor-1α (HIF1A). In vitro and in vivo functional assays, including Cell Counting Kit-8 (CCK-8), Transwell, chicken chorioallantoic membrane (CAM), and xenograft, were conducted to evaluate proliferation, migration, invasion, and angiogenesis. Mechanistic studies, including chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), luciferase reporter, and actinomycin D assay, were conducted to elucidate HIF1-mediated transcriptional regulation of TARDBP and TDP-43-dependent stabilization of thyroid receptor-interacting protein 6 (TRIP6) mRNA. As a result, TDP-43 was upregulated in CRC tissues and correlated with HIF1A expression. Hypoxia induced TDP-43 expression through HIF1-dependent transcriptional activation via direct binding to hypoxia-response element (HRE) 3 site in the TARDBP promoter. TARDBP knockdown suppressed hypoxia-induced proliferation, migration, invasion, and vascular endothelial growth factor (VEGF) secretion, which were rescued by HIF1A overexpression. RIP-qPCR revealed TDP-43 binding to TRIP6 mRNA via its RNA recognition motifs (RRM domains), stabilizing TRIP6 transcripts and promoting its expression. TRIP6 reconstitution reversed the anti-tumor effects of TARDBP silencing. In vivo, TARDBP depletion inhibited tumor growth and downregulated metastasis-related factors in xenograft models. In conclusion, the HIF1-TARDBP-TRIP6 axis promotes CRC malignancy under hypoxia by integrating transcriptional activation and post-transcriptional mRNA stabilization, offering potential therapeutic targets for advanced CRC.
Bibliometric and visual analysis: A comprehensive tracking of global research trends on ablation and tumor immune microenvironment from 2016 to 2025.
Meng S, Li J, Cao F … +1 more , Niu H
Transl Oncol · 2026 Aug · PMID 42275679 · Full text
OBJECTIVE: This study aims to gain an understanding the relationship between ablation and the tumor immune microenvironment. A bibliometric and visual analysis was conducted on relevant researches in this field over the...
OBJECTIVE: This study aims to gain an understanding the relationship between ablation and the tumor immune microenvironment. A bibliometric and visual analysis was conducted on relevant researches in this field over the past decade. MATERIALS AND METHODS: As of February 21, 2026, the research team conducted a literature search using the Web of Science Core Collection (WoSCC) database. Two researchers independently carried out the search. After screening, a total of 5328 papers were selected for analysis. Citespace 6.4.R1, VOSviewer 1.6.18, and Bibliomatrix R software were used for bibliometric analysis and visualization. RESULTS: An analysis of research on ablation and the tumor immune microenvironment from 2016 to 2025 shows that China leads the world in the number of published articles and has extensive international cooperation. Chinese research authors, highly cited articles, and research institutions have all performed outstandingly. The study also reviewed the literature on the synergistic effects of ablation and immunotherapy, indicating the dynamic changes in research hotspots in this field. CONCLUSION: The combination of immunotherapy and ablation is expected to become an effective treatment method for tumors. Ablation has evolved from local destruction to a core tumor treatment strategy that reshapes the immune microenvironment, and its combination with immunotherapy further demonstrates tremendous translational potential and clear clinical value.
Programmed death 1 antibody drug conjugates (PD 1 ADCs): Innovations in overcoming resistance and enhancing immune mediated antitumor activity.
Tian Z
Transl Oncol · 2026 Aug · PMID 42275678 · Full text
Programmed death-1 (PD-1) antibody-drug conjugates (ADCs) are a new generation of immune checkpoint blockers, which incorporate the delivery of cytotoxic drug targets. The objectives of these ADCs are to selectively targ...
Programmed death-1 (PD-1) antibody-drug conjugates (ADCs) are a new generation of immune checkpoint blockers, which incorporate the delivery of cytotoxic drug targets. The objectives of these ADCs are to selectively target cells in the tumor microenvironment expressing PD-1, causing tumor cells to die, rejuvenating T cell exhaustion, and destroying immunosuppressive cells. PD-1 ADCs aim to address the shortcomings of conventional PD-1 inhibitors, which may be resistant in certain cancers, by harnessing a two-pronged mechanism. This method can also be used to boost antitumor immunity by stimulating the activation and expansion of immune effector cells. Despite promising preclinical and early clinical outcomes, multiple issues remain in the development of PD-1 ADCs, including heterogeneity in tumor antigens, the development of resistance mechanisms, and instability of the ADC linker. Current studies are trying to overcome these challenges by improving ADC engineering, cytotoxic payload optimization, and investigating combination therapy. PD-1 ADCs, with their capacity to specifically regulate immunity and deliver potent cytotoxic drugs directly to tumor cells, have the potential to provide a valuable treatment modality. This would be beneficial for clinical outcomes, especially in cancers resistant to traditional treatment methods, and it represents a great step forward in cancer immunotherapy.
Telomerase-related gene EHHADH drives lung cancer progression and shapes the immunosuppressive tumor microenvironment.
Wei W, Wang Y, Abudukeremu D … +2 more , Luo J, Du M
Transl Oncol · 2026 Aug · PMID 42269569 · Full text
BACKGROUND: Lung cancer is a leading cause of cancer-related mortality, necessitating accurate prognostic assessment and optimized treatment. Telomerase-related genes are pivotal in tumor development, yet their prognosti...
BACKGROUND: Lung cancer is a leading cause of cancer-related mortality, necessitating accurate prognostic assessment and optimized treatment. Telomerase-related genes are pivotal in tumor development, yet their prognostic value and mechanisms within the lung cancer tumor microenvironment (TME) remain unclear. METHODS: We analyzed telomerase-related gene mutations in lung cancer (TCGA) and identified eight key prognostic genes (INMT, ALDH3A2, OGDHL, TDO2, EFNA3, STAT1, EHHADH, AANAT) from seven public datasets via Cox regression. A robust prognostic risk model was built and validated across independent cohorts. TME associations were explored using IPS, ESTIMATE scores, and immune infiltration analyses. EHHADH's functional role was validated via immunohistochemistry, in vitro knockdown, and single-cell RNA sequencing. RESULTS: Our model demonstrated strong predictive performance and consistently outperformed existing prognostic signatures across multiple datasets. Importantly, low-risk patients exhibited an "immune-hot" phenotype with higher IPS scores and enhanced immune cell infiltration, suggesting potential sensitivity to immunotherapy. In contrast, high-risk patients displayed an immunosuppressive microenvironment. Among the model genes, EHHADH emerged as a key oncogenic driver, positively associated with risk score and poor survival. Functional assays revealed that EHHADH promotes tumor cell migration while reducing adhesion. Single-cell analysis further demonstrated that EHHADH is predominantly expressed in epithelial cells and is associated with an "immune-desert" TME characterized by reduced immune infiltration. CONCLUSION: This study establishes a clinically relevant telomerase-related gene signature that enables effective risk stratification and provides insights into tumor-immune interactions in lung cancer. Notably, EHHADH is identified as a potential therapeutic target that contributes to immune evasion and tumor progression. These findings offer a foundation for personalized prognostic assessment and suggest that targeting EHHADH may enhance the efficacy of immunotherapy in lung cancer patients.
TFF1-mediated suppression of the TCA cycle promotes bone metastasis in triple-negative breast cancer.
Chen H, Xu Y, Liu Y … +6 more , Tang Y, Qiu J, Lei L, Lin P, Chen Y, Wu X
Transl Oncol · 2026 Aug · PMID 42263468 · Full text
Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterized by limited treatment options and poor prognosis. While TNBC exhibits a lower incidence of bone metastasis compared to lum...
Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterized by limited treatment options and poor prognosis. While TNBC exhibits a lower incidence of bone metastasis compared to luminal subtypes, its occurrence is associated with substantial morbidity and mortality. The metabolic mechanisms enabling TNBC cells to colonize bone remain largely undefined. In this study, a bone-tropic TNBC subline (MDA-MB-231/BM) was developed through iterative intracardiac inoculation in mice, followed by transcriptomic profiling to identify genes with altered expression. A CRISPR/Cas9 knockout library screen in MDA-MB-231 cells further revealed critical regulators of bone metastasis. Notably, dual-omics analysis demonstrated a consistent downregulation of key enzymes in the tricarboxylic acid (TCA) cycle within bone-metastatic TNBC cells. Functional experiments showed that PDHA1 knockout impaired cell migration, invasion, and mitochondrial respiration, underscoring the TCA cycle's essential role in metastasis. Among the identified regulators, TFF1 emerged as a potent suppressor of TCA cycle gene expression. Deletion of TFF1 enhanced mitochondrial function, reduced metastatic burden in vivo, and extended survival in mouse models. Supporting clinical relevance, TCGA data showed significantly higher TFF1 expression in luminal breast cancer compared to TNBC, aligning with the greater propensity for bone metastasis in luminal subtypes. These findings reveal that TFF1-mediated suppression of the TCA cycle contributes to the metabolic adaptation of TNBC cells for bone colonization, offering a potential therapeutic vulnerability and advocating for subtype-specific metabolic interventions.
Pharmacological inhibition of LIF signaling reverses PD-L1-mediated immune suppression in gastric cancer.
Di Giorgio C, Marchianò S, Biagioli M … +16 more , Lachi G, Massa C, Sensini B, Giannelli E, Sette MR, Urbani G, Paniconi F, Cari L, Monti MC, Sepe V, Natalizi N, Graziosi L, Distrutti E, Donini A, Zampella A, Fiorucci S
Transl Oncol · 2026 Aug · PMID 42259194 · Full text
INTRODUCTION: Gastric cancer (GC) is a major clinical challenge, characterized by limited response rates to immune checkpoint inhibitors (ICIs) and persistent immune evasion. Leukemia Inhibitory Factor (LIF), an IL-6 fam...
INTRODUCTION: Gastric cancer (GC) is a major clinical challenge, characterized by limited response rates to immune checkpoint inhibitors (ICIs) and persistent immune evasion. Leukemia Inhibitory Factor (LIF), an IL-6 family cytokine, reshapes the tumor microenvironment, yet its contribution to PD-L1-mediated immune suppression in GC has not been investigated. MATERIAL AND METHODS: LIF and PD-L1 expression were quantified in resected GC specimens and matched mucosa by immunohistochemistry and gene expression (Log2), and their associations with clinicopathological variables and survival were evaluated. GC cell lines were exposed to recombinant LIF and to anovel LIF antagonist, LRI-305. Activation of the JAK1/STAT3 pathway, PD-L1 transcription and protein and epithelial-mesenchymal transition (EMT) markers were analyzed. By t-SNE analysis we profiled LIF⁺/PD-L1⁺ cell subsets across myeloid and non-haematopoietic compartments, and by functional assays we have assessed whether LIF blockade modulates T cell activation. RESULTS: LIF expression was significantly elevated in GC tissues and correlates with poor prognosis and increased PD-L1 levels. LIF promotes immune escape by activating the JAK1/STAT3 pathway, leading to transcriptional upregulation of PD-L1 and enhancement of EMT. The t-SNE analysis revealed that LIF⁺/PD-L1⁺ myeloid and non-hematopoietic cells were enriched in the neoplastic mucosa. Pharmacological blockade of LIF signaling effectively suppressed STAT3 phosphorylation and downregulated PD-L1 expression. LRI-305 treatment partially restored immune activation signatures, supporting its potential as a therapeutic adjuvant to ICIs. DISCUSSION: LIF/STAT3 enhances PD-L1 expression and participate to GC immune evasion. Targeting LIF signaling could be a strategy to overcome resistance to immunotherapy.
Variation in LINE-1 ORF1p expression across histologic and demographic subgroups in non-small cell lung cancers.
Wang Y, Li C, Nguyen K … +3 more , Powell R, Kondapaneni M, Ramos KS
Transl Oncol · 2026 Aug · PMID 42259192 · Full text
Aberrant activation of Long Interspersed Element-1 (LINE-1) retrotransposons and their encoded proteins has been linked to poor clinical outcomes across multiple malignancies, including non-small cell lung cancers (NSCLC...
Aberrant activation of Long Interspersed Element-1 (LINE-1) retrotransposons and their encoded proteins has been linked to poor clinical outcomes across multiple malignancies, including non-small cell lung cancers (NSCLC). In this study, we profiled LINE-1 ORF1p expression and its co-localization with immune cells using multiplex immunofluorescence of NSCLC tumors and matched adjacent non-tumor tissues (N = 76). These data were then integrated with clinicopathologic features to assess the potential clinical utility of such measurements. ORF1p expression was significantly elevated in NSCLC compared to non-tumor lung tissues, with higher levels in lung squamous cell carcinoma (LSQCC) than in lung adenocarcinoma (LUAD). Race-stratified analyses showed markedly higher ORF1p levels in African American compared with Caucasian American patients. Although sex-based differences were less consistent, older males exhibited significantly higher ORF1p levels than other subgroups. Age-stratified analyses revealed a positive correlation between ORF1p and increasing age in tumor samples. Co-expression analyses combined with cellular neighborhood enrichment and spatial auto-correlation analyses demonstrated that ORF1p was most strongly associated with CD68⁺ macrophages across both tumor subtypes and representing the most reliably enriched immune cell population in the immediate spatial vicinity of tumor cells with high ORF1p expression. These findings indicate that LINE-1 ORF1p expression in NSCLC is shaped by tumor histology, race, and age, and may be influenced by macrophage-LINE-1 interactions within the tumor microenvironment.
Integrative single-cell and spatial transcriptomics analysis reveals a baicalein-responsive 10-gene signature for non-small cell lung cancer.
Wu D, Liu C, Zhan L … +3 more , Liang M, Li Q, Lian Q
Transl Oncol · 2026 Aug · PMID 42251782 · Full text
BACKGROUND: Non‑small cell lung cancer (NSCLC) remains a leading cause of cancer‑related mortality worldwide. Baicalein, a natural flavonoid, has shown anti‑cancer activity but its molecular targets and cell‑type‑specifi...
BACKGROUND: Non‑small cell lung cancer (NSCLC) remains a leading cause of cancer‑related mortality worldwide. Baicalein, a natural flavonoid, has shown anti‑cancer activity but its molecular targets and cell‑type‑specific effects in the tumor microenvironment (TME) are incompletely understood. METHODS: We integrated network pharmacology, single‑cell RNA‑seq, bulk transcriptomics, spatial transcriptomics, machine learning, and in vitro experiments to identify baicalein‑responsive genes in NSCLC. RESULTS: Single‑cell analysis resolved 21 cell populations, revealing that baicalein targets were enriched in a 32‑gene core set. Consensus clustering defined three molecular subtypes (cluster 1-cluster 3) with distinct immune infiltration; cluster 1 showed an immune‑cold phenotype with upregulation of cell cycle and metabolic pathways, while cluster 3 was immune‑hot. Machine learning selected a 10‑gene signature (TOP2A, CDH1, CCNB1, SATB2, CA9, HMGB2, MB, NQO1, AURKB, CCNB2) with high diagnostic accuracy. SHAP analysis identified TOP2A as the most influential contributor. Spatial transcriptomics confirmed significantly elevated expression of all ten genes in tumor versus adjacent/normal tissues. Cell‑cell communication analysis highlighted enhanced MIF pathway signaling in the TME, with epithelial cells and SPP1+ TAMs acting as key senders. Molecular docking showed strong binding affinities (ΔG ≤ -8.5 kcal/mol) between baicalein and AURKB, MB, TOP2A, and CCNB2, and molecular dynamics simulations further confirmed the stability of these complexes. In vitro, baicalein (30 μM, 24 h) differentially modulated signature gene expression in PC‑9 and A549 cells and suppressed viability in a dose‑ and time‑dependent manner. CONCLUSIONS: This integrative study provides a comprehensive single‑cell and spatial atlas of baicalein‑responsive genes in NSCLC, identifies a robust diagnostic signature, and offers mechanistic insights for developing baicalein as a potential therapeutic agent.
Multi-regional transcriptomics reveals robust consensus subtypes beyond tumor heterogeneity of breast cancer.
Ji J, Zheng Q, Li X … +2 more , Luo C, Wang J
Transl Oncol · 2026 Aug · PMID 42247929 · Full text
BACKGROUND: Commercial molecular classifiers such as Prediction Analysis of Microarray 50 (PAM50), Oncotype DX, and MammaPrint have revolutionized breast cancer management. However, their clinical reliability is undermin...
BACKGROUND: Commercial molecular classifiers such as Prediction Analysis of Microarray 50 (PAM50), Oncotype DX, and MammaPrint have revolutionized breast cancer management. However, their clinical reliability is undermined by tumor heterogeneity. METHODS: We quantified the discordance in clinical molecular typing across multi-regional samples. Gene set enrichment analysis (GSEA) was employed to explore potential sources of intratumoral heterogeneity (ITH). Gene-level heterogeneity was evaluated by quantifying expression variation within versus between tumors. A robust subtyping framework was constructed via Non-negative Matrix Factorization (NMF) based on a screened low-ITH gene set. RESULTS: ITH was observed in over 50% of tumors, triggering significant classification discordance across commercial tests. GSEA revealed that transcriptomic heterogeneity might be driven by stromal and matrix-related pathways. The low-ITH-based NMF framework established an optimal three-subtype classification that exhibited superior prognostic stratification and maintained high stability across metastatic sites. CONCLUSIONS: We established a low-ITH subtyping framework that overcomes the limitations of single-biopsy-based molecular typing. Our findings offer a novel strategy to enhance the precision of breast cancer management.
Multi-omics analysis identifies CKLF as a promoter for HCC progression by regulating the AKT, ERK pathways, and infiltrating immune cells.
Peng L, Li J, Yuan J … +4 more , Ma S, Jin L, Zou G, Tang L
Transl Oncol · 2026 Aug · PMID 42241992 · Full text
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly malignant disease with limited therapeutic options, highlighting an urgent need to identify novel molecular regulators and potential intervention points. METHODS: We...
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly malignant disease with limited therapeutic options, highlighting an urgent need to identify novel molecular regulators and potential intervention points. METHODS: We normalized single-cell data using SCTransform and removed batch effects with Harmony. Cell-cell communication was predicted using CellChat, and spatial cell-type mapping was performed using RCTD algorithms. For functional characterization, we conducted in vitro experiments including CKLF silencing via siRNA, followed by proliferation assays (CCK-8),Immunohistochemistry, wound healing, and colony formation assays. To verify the involved pathways, we performed complementary studies using constitutively active Ras mutants. RESULTS: CKLF was found to be upregulated in HCC tissues, and high CKLF levels correlated significantly with advanced pathological stages, distinct molecular classes, and poor clinical outcomes. Single-cell and spatial analyses revealed that CKLF is highly expressed not only in the hepatocellular compartment but also in infiltrated immune cells with a cytotoxic signature (CD8+ T cells and M1 macrophages), suggesting an impact on both tumor cells and immunity. CKLF knockdown significantly reduced tumor proliferation, motility, and colony-forming ability in HCC models in vitro. These effects were at least partly rescued by persistent Ras pathway activation, confirming that CKLF acts upstream to regulate the AKT/ERK pathway. CONCLUSIONS: These results demonstrate that CKLF is a critical node linking gene copy number changes, oncogenic signaling pathways, and immunophenotypic alterations in hepatocellular carcinoma. Thus, CKLF represents a promising biomarker and therapeutic target for providing individualized therapies to HCC patients.
A pan-cancer landscape of LILRB4 identifies it as a context-dependent marker of the myeloid and antigen-presentation axis.
Li J, He X, Guo Y … +3 more , Zhang L, Cheng W, Zheng C
Transl Oncol · 2026 Aug · PMID 42241991 · Full text
Inhibitory receptors modulate antigen presentation and myeloid responses within the tumor microenvironment, yet the cross-cancer landscape and clinical significance of LILRB4 remain incompletely defined. By integrating p...
Inhibitory receptors modulate antigen presentation and myeloid responses within the tumor microenvironment, yet the cross-cancer landscape and clinical significance of LILRB4 remain incompletely defined. By integrating public multi-omics resources, we systematically profiled LILRB4 across expression, genetic alterations, DNA methylation, phosphorylation, and immune infiltration, and examined their associations with clinical outcomes. LILRB4 is enriched in immune tissues and in monocytes, macrophages, and dendritic cells, and is upregulated in multiple cancers, with occasional discordance between transcript and protein levels. Its association with survival is cancer-type dependent-protective in cervical cancer, skin cutaneous melanoma, and uterine carcinosarcoma, but associated with higher risk in lower-grade glioma and recurrence-related metrics of prostate adenocarcinoma. Genetic alterations are dominated by amplification and missense mutations clustering within immunoglobulin domains, including a P184 hotspot, yet carriers do not show consistent survival differences. LILRB4 expression positively correlates with tumor mutational burden, microsatellite instability, and homologous recombination deficiency in several cancers. In lower-grade glioma, hypermethylation at a promoter-proximal CpG site associates with longer survival, and multiple cancers display site- and cancer-specific phosphorylation differences. LILRB4 correlates strongly with macrophage infiltration, and co-expression and interaction analyses converge on antigen processing and presentation pathways, with HLA-DRA emerging as a shared node. Collectively, these findings support LILRB4 as a context-dependent marker of the myeloid and antigen-presentation axis in the tumor microenvironment and provide an integrated reference framework that warrants further functional validation.
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