Translational Oncology[JOURNAL]
Sun
200 papers
Multi-Omics profiling identify NNMT in tumor endothelium as a key regulator of CD8⁺ T cell exhaustion via the TGF signaling pathway.
Wang L, He H, Su K … +7 more , Gao Y, Luo Y, Tan H, Liu Z, Xu K, Li Y, Li X
Transl Oncol · 2026 Jul · PMID 42140035 · Full text
BACKGROUND: CD8⁺ T cell exhaustion is a defining feature of the immunosuppressive TME in ccRCC. METHODS: We employed a multi-omics driven pipeline to nominate Nicotinamide N-methyltransferase (NNMT) as a high-confidence...
BACKGROUND: CD8⁺ T cell exhaustion is a defining feature of the immunosuppressive TME in ccRCC. METHODS: We employed a multi-omics driven pipeline to nominate Nicotinamide N-methyltransferase (NNMT) as a high-confidence therapeutic target in ccRCC. This computational prediction was validated through bulk RNA-seq, single-cell RNA sequencing, and spatial transcriptomics to delineate NNMT-associated molecular and cellular programs. While the discovery phase highlighted endothelial-specific NNMT overexpression, we further validated the functional consequences of NNMT modulation using Caki-1 and A498 cell lines to model the downstream signaling cascades. Functional assays assessed impacts on proliferation, apoptosis, cytokine secretion (IL-6, IL-1β, TNF-α), and TGF-β pathway activity. Immune infiltration and T cell exhaustion signatures were evaluated across TCGA cohorts. RESULTS: Multi-omics profiling revealed that NNMT is specifically overexpressed in tumor-associated endothelial cells enriched for active TGF-β signaling and inflammatory cues. High NNMT expression strongly correlated with CD8⁺ T cell exhaustion, elevated apoptotic signaling, and immunosuppressive cytokine production. In functional validation, NNMT knockdown suppressed TGF-β activity, reduced pro-inflammatory cytokines, and restored CD8⁺ T cell infiltration and effector function. Mechanistically, NNMT loss shifted the BAX/Bcl-2 ratio toward apoptosis and increased cleaved caspase-3. Spatial transcriptomics confirmed that NNMT⁺ endothelial cells form an immunosuppressive niche in direct contact with exhausted T cells. We also found that I-BET-762, I-BET-151, PFI-1, and BMS-387032 can target and inhibit NNMT to reduce CD8⁺ T cell exhaustion. CONCLUSION: We establish NNMT as a central metabolic-immune hub that orchestrates TGF-β-mediated CD8⁺ T cell dysfunction and endothelial reprogramming in ccRCC.
JOSD1 stabilizes SULF1 to activate Wnt7B-FZD1 signaling in gastric cancer.
Liu L, Ma Z, Zhang Y … +4 more , Ye Z, Li H, Shi W, Jiao Z
Transl Oncol · 2026 Jul · PMID 42140034 · Full text
BACKGROUND: Aberrant activation of Wnt/β-catenin signaling is a major driver of Gastric cancer (GC) progression. However, the upstream mechanisms that sustain receptor-ligand engagement within this pathway remain insuffi...
BACKGROUND: Aberrant activation of Wnt/β-catenin signaling is a major driver of Gastric cancer (GC) progression. However, the upstream mechanisms that sustain receptor-ligand engagement within this pathway remain insufficiently characterized. METHODS: Comprehensive analyses of GC cohorts and tissue microarrays were performed to evaluate Josephin Domain Containing 1 (JOSD1) expression and its clinical significance. The impact of JOSD1 on cell proliferation, migration, invasion, apoptosis, and epithelial mesenchymal transition (EMT) was examined in vitro employing CCK-8, colony formation, Transwell, flow cytometry, Western blotting, and immunofluorescence assays. Subcutaneous xenograft models were used to assess the effects of JOSD1 on tumor growth in vivo. Mechanistic studies, including co-immunoprecipitation, ubiquitination, and rescue experiments, were employed to elucidate the molecular relationship between JOSD1, Heparan sulfate 6-O-endosulfatase 1 (SULF1), and the Wnt7B/FZD1/β-catenin signaling axis. RESULTS: JOSD1 expression was markedly elevated in GC tissues (log₂ FC > 1, FDR < 0.05) and correlated with advanced stage (P < 0.05) and poor patient prognosis (HR > 1, log-rank P < 0.05). Functionally, JOSD1 promoted GC cell proliferation, invasion, and EMT, while inhibiting apoptosis (P < 0.05). Mechanistically, JOSD1 functioned as a critical deubiquitinase that stabilized SULF1. Stabilized SULF1 directly bound the Wnt co-receptor Frizzled class receptor 1 (FZD1) and facilitated Wnt7B-FZD1 complex formation (P < 0.05), thereby activating canonical Wnt/β-catenin signaling and inducing β-catenin nuclear accumulation (P < 0.05). Ubiquitination and rescue assays confirmed that JOSD1-driven oncogenic effects were strictly dependent on SULF1 stabilization (P < 0.05). In vivo modulation of the JOSD1-SULF1 axis significantly altered tumor growth, apoptotic activity, EMT marker expression, and Wnt pathway activation (P < 0.05). CONCLUSION: JOSD1 functions as a critical deubiquitinase that stabilizes SULF1 to activate Wnt/β-catenin signaling, thereby driving GC progression. Targeting the JOSD1-SULF1-Wnt7B/FZD1/β-catenin axis may provide a promising therapeutic strategy for patients with GC.
Multi-omics interrogation identifies IRF4 as a causal transcription factor in monocytes that suppresses colorectal cancer progression by remodeling the immune microenvironment and inhibiting EMT.
Wen H, Li F, He Q … +9 more , Liu K, Zhang X, Zhu Y, Ge T, Rong M, Hu R, Xi H, Zheng P, Liu S
Transl Oncol · 2026 Jul · PMID 42140033 · Full text
BACKGROUND: Although surgery and chemotherapy remain standard treatments for colorectal cancer (CRC), immunotherapy offers a promising avenue for patients with advanced disease. However, the cellular and molecular mechan...
BACKGROUND: Although surgery and chemotherapy remain standard treatments for colorectal cancer (CRC), immunotherapy offers a promising avenue for patients with advanced disease. However, the cellular and molecular mechanisms underlying CRC progression and immune evasion are not fully elucidated. METHODS: We integrated single-cell RNA sequencing (GSE161277), bulk transcriptomic data (GEO and TCGA), and Mendelian randomization (MR) analysis to identify key cell subpopulations and transcription factors (TFs) causally associated with CRC. Spatial transcriptomics, multiple immune deconvolution algorithms, and in vitro experiments (including lentiviral-mediated IRF4 modulation, flow cytometry, and ELISA) were performed to validate the expression, immune regulatory function, and prognostic significance of the candidate TF. RESULTS: Single-cell analysis identified monocytes as the most critical cell subpopulation in CRC pathogenesis. MR analysis revealed that IRF4, monocyte-associated TF, was causally linked to increased CRC risk. IRF4 expression was significantly downregulated in CRC tissues at both mRNA and protein levels, with elevated methylation and association with poor prognosis. Multi-omics immune profiling demonstrated that IRF4 correlated with immune cell infiltration, cancer immunity cycle scores, and immunotherapy response. Spatially, IRF4 was enriched in normal or low-malignant regions. Experimentally, IRF4 overexpression in HCT116 CRC cell enhanced CXCL8 and CCL5 secretion, increased the number of CD14IRF4 monocytes and CD3CD8IRF4 T cells in co-culture systems, and suppressed epithelial-mesenchymal transition (EMT), whereas IRF4 knockdown reversed these effects. CONCLUSIONS: IRF4, monocyte-associated TF, is a causal factor in CRC development. Its downregulation correlates with adverse prognosis and impaired antitumor immunity. IRF4 modulates the tumor microenvironment by regulating chemokine secretion, immune cell recruitment, and EMT, positioning it as a potential therapeutic target for CRC immunotherapy.
Integrating spatial and single-cell transcriptomics via machine learning to characterize efferocytosis in hepatocellular carcinoma prognosis and immunotherapy.
Yi Q, Zhou B, Gu X … +5 more , Ma Z, Pan B, Yuan Z, Wen W, Lu C
Transl Oncol · 2026 Jul · PMID 42140032 · Full text
BACKGROUND: The intratumoral heterogeneity and immunosuppressive microenvironment of hepatocellular carcinoma (HCC) significantly limit therapeutic efficacy. Although efferocytosis is fundamental for tissue homeostasis,...
BACKGROUND: The intratumoral heterogeneity and immunosuppressive microenvironment of hepatocellular carcinoma (HCC) significantly limit therapeutic efficacy. Although efferocytosis is fundamental for tissue homeostasis, its impact on the spatial architecture of the tumor microenvironment (TME) and patient prognosis in HCC remains uncharacterized. METHODS: We integrated single-cell RNA sequencing, spatial transcriptomics, and large-scale bulk datasets to construct an Efferocytosis-Related Scoring System (ERG score). We identified molecular subtypes and traced key cell subsets driving high-efferocytosis features. A robust prognostic model was established via large-scale machine learning screening (101 algorithms) and validated by in vitro experiments (qRT-PCR/Western Blot). RESULTS: The ERG score indicates a specific immunosuppressive state driven by the High_ERGs_SPP1_Mac subpopulation. Spatially, this subpopulation physically co-localizes with malignant cells, potentially mediated by the MDK-SDC2 axis. The machine learning-derived risk score serves as a reliable quantitative indicator of High_ERGs_SPP1_Mac abundance, effectively predicting "cold tumor" phenotypes and immune checkpoint upregulation (e.g., PD-1, CTLA4). Additionally, experimental validation confirmed the upregulation of the core gene TPI1 (triosephosphate isomerase 1), aligning with the high glycolytic features of the high-risk subtype. CONCLUSION: The ERG scoring system offers a novel perspective for deconvoluting HCC heterogeneity. Our findings suggest that SPP1+ macrophages spatially reshape the TME, providing a theoretical basis for optimizing prognostic stratification and personalized immunotherapy.
An ac4C-CDK4 regulatory axis driven by NAT10 sustains proliferative signaling in colorectal cancer.
Qin J, Shen Y, Li S … +5 more , Hu S, Song F, Jin T, Wu J, Xu J
Transl Oncol · 2026 Jul · PMID 42127733 · Full text
BACKGROUND: N-acetyltransferase 10 (NAT10) is an RNA acetyltransferase that catalyzes N4-acetylcytidine (ac⁴C) modification and regulates mRNA stability. However, its biological function and mechanistic role in colorecta...
BACKGROUND: N-acetyltransferase 10 (NAT10) is an RNA acetyltransferase that catalyzes N4-acetylcytidine (ac⁴C) modification and regulates mRNA stability. However, its biological function and mechanistic role in colorectal cancer (CRC) remain poorly defined. METHODS: NAT10 expression was analyzed across multiple GEO cohorts and paired CRC clinical specimens. Gain- and loss-of-function experiments were performed to assess the effects of NAT10 on CRC cell proliferation, migration, colony formation, and tumor growth in vivo. Transcriptomic correlation and enrichment analyses were used to identify NAT10-associated pathways. RIP-seq mining, NAT10-RIP-qPCR, and ac⁴C-RIP-qPCR were applied to verify downstream targets. Actinomycin D chase assays were used to evaluate mRNA stability. The functional relevance of CDK4 was examined using genetic NAT10 perturbation, Remodelin-based pharmacologic treatment, and CDK4 rescue experiments. RESULTS: NAT10 was markedly up-regulated in CRC tissues compared with normal mucosa and was maintained at high levels in malignant CRC lesions. NAT10 overexpression enhanced CRC cell proliferation, migration, and colony formation, whereas NAT10 knockout suppressed these phenotypes. In vivo, NAT10-deficient cells formed significantly smaller and slower-growing xenograft tumors, with markedly reduced tumor volume and weight compared with controls. Pathway analyses indicated strong enrichment of cell-cycle programs, particularly the G1/S transition. CDK4 was identified as a NAT10-associated ac⁴C-modified target. NAT10 depletion destabilized CDK4 mRNA, reduced CDK4-associated cell-cycle protein expression, and induced G1/S accumulation, while NAT10 overexpression produced the opposite effects. Remodelin treatment, used as a pharmacologic perturbation of NAT10-associated signaling, suppressed CDK4 expression and CRC cell growth, and CDK4 overexpression partially rescued these inhibitory effects. CONCLUSIONS: This study identifies a mechanistic NAT10-ac⁴C-CDK4 regulatory axis that stabilizes CDK4 mRNA, promotes G1/S transition, and drives CRC progression. Targeting NAT10 or its downstream CDK4 pathway represents a potential therapeutic strategy for CRC.
A positive feedback loop between CDH11 and TGF-β signaling regulates migration and invasion of gastric cancer.
Yan Q, Yu S, Dong Y … +4 more , Qing S, Song Q, Yao Y, Li Y
Transl Oncol · 2026 Jul · PMID 42127732 · Full text
OBJECTIVE: To investigate the molecular functions and underlying mechanisms of cadherin 11 (CDH11) in the pathogenesis of advanced gastric cancer (GC), and to evaluate the therapeutic potential of targeting CDH11 and its...
OBJECTIVE: To investigate the molecular functions and underlying mechanisms of cadherin 11 (CDH11) in the pathogenesis of advanced gastric cancer (GC), and to evaluate the therapeutic potential of targeting CDH11 and its associated signaling pathways. METHODS: The clinicopathological significance of CDH11 in GC was analyzed using the TCGA database. Experiments were conducted to assess the impact of genetic variations on the function of GC cell lines. The therapeutic potential of targeting CDH11 was evaluated in vitro and in vivo. The clinical relevance of CDH11 expression was further validated. RESULTS: TCGA analysis showed that CDH11 was highly expressed in GC and served as an independent prognostic biomarker. High CDH11 expression was also associated with a potentially immunosuppressive tumor microenvironment (TME) in GC. Mechanistically, CDH11 promoted epithelial-mesenchymal transition (EMT) and GC progression by upregulating TGF-β1 and activating TGF-β signaling. Activated TGF-β signaling enhanced CDH11 transcription via the binding of the downstream transcription factor Snail2 to the CDH11 promoter, thereby forming a positive regulatory loop. The targeting of CDH11/TGF-β signaling significantly suppressed migration and invasion of GC in vitro and lung metastasis of GC in vivo. Clinically, CDH11 and Vimentin were highly expressed in GC, especially in the diffuse-type cases, and a positive correlation between them was also identified. In the clinical samples, CDH11 was positively correlated with M2 macrophage marker CD163 and immune checkpoint PD-L1. CONCLUSION: The present study identifies a novel positive feedback loop between CDH11 and TGF-β signaling, which critically regulates EMT, migration, invasion and metastasis of GC cells. The targeting of this axis may represent a promising therapeutic strategy for GC.
Single-cell RNA sequencing reveals immune microenvironment heterogeneity in BRCA1-mutated and sporadic triple-negative breast cancer.
Sun Q, Zhong Y, Sun C
Transl Oncol · 2026 Jul · PMID 42119173 · Full text
Immune checkpoint blockade has shown benefit in some Triple-negative breast cancer (TNBC) patients, but responses are variable. BRCA1-mutated TNBC represents a biologically distinct subgroup, potentially differing in imm...
Immune checkpoint blockade has shown benefit in some Triple-negative breast cancer (TNBC) patients, but responses are variable. BRCA1-mutated TNBC represents a biologically distinct subgroup, potentially differing in immunogenicity and immunotherapy responsiveness. However, immune microenvironment differences between BRCA1-mutated and sporadic TNBC remain incompletely understood. By performing single-cell RNA sequencing analysis on sporadic TNBC and BRCA1 mutant TNBC, we assessed immune cell composition, transcriptional program, pathways, stemness, differentiation, and transcription factor regulatory networks. B cell and plasma cell subtypes were further explored using AUCell, CytoTRACE, Monocle2, and Slingshot. Compared to sporadic TNBC, BRCA1-mutated TNBC exhibited a distinct immune landscape with enriched naïve and memory B cells, while sporadic TNBC was dominated by terminally differentiated plasma cells, including IgA plasma cells. Functional enrichment analyses showed enhanced adaptive immune signaling, antigen presentation, and B cell receptor pathways in BRCA1-mutated TNBC, while sporadic TNBC had humoral effector and immunoregulatory programs. Trajectory and stemness analyses indicated enhanced cellular plasticity and decreased differentiation in B cells derived from BRCA1-mutated triple-negative breast cancer. Analysis of transcription factors revealed JUND and ETV1 in BRCA1-mutated TNBC, and MEIS1 and CEBPB in sporadic TNBC. Our findings underscore disparities in the immune ecosystem between BRCA1-mutated and spontaneous TNBC, indicating that the B cell-centric immunological milieu in BRCA1-mutated TNBC may offer a more advantageous setting for immunotherapy. Sporadic TNBC, by contrast, exhibits an immunological state characterized by plasma cells, which may restrict immune reactivation. These data indicate that B cell-based immunological stratification may guide precision immunotherapy approaches.
Feiyanning formula inhibits metastasis and differentiation of osteoclasts by targeting miR-328/NF-κB signaling axis via exosomal HOTAIR in lung cancer cells.
Zhang C, Liu Y, Lu Z … +13 more , Qin J, Yang L, Yin Q, Rao Z, Ji J, Chen K, Su W, Zhan X, Jin J, Ben W, Zhou Z, Huang X, Wang Z
Transl Oncol · 2026 Jul · PMID 42114285 · Full text
As one of the most lethal malignant tumors worldwide, the highly invasive and metastatic nature of lung cancer leads to a generally poor prognosis for patients. Among the complications associated with lung cancer, skelet...
As one of the most lethal malignant tumors worldwide, the highly invasive and metastatic nature of lung cancer leads to a generally poor prognosis for patients. Among the complications associated with lung cancer, skeletal-related events (SREs) resulting from bone metastases, including bone pain, pathological fractures, hypercalcemia, and spinal cord compression, significantly impair quality of life and reduce survival rates. The long non-coding RNA HOTAIR, which has been linked to various cancers, plays an unclear role in lung cancer bone metastasis and the regulation of the immune microenvironment. In this study, we investigated the expression of HOTAIR in non-small cell lung cancer (NSCLC) and its impact on the immune microenvironment using bioinformatics, microscopy, and functional assays. Our findings indicate that elevated HOTAIR expression is associated with poorer prognosis based on transcriptomic analyses. Bioinformatics validation in independent GEO datasets and clinical tissue samples also confirmed the prognostic value of HOTAIR in NSCLC bone metastasis subgroups. Mechanistically, HOTAIR expression was correlated with alterations in immune cell infiltration patterns, including reduced B-cell and CD8+ T-cell signatures, and was accompanied by increased NF-κB and ERBB pathway activity. These observations suggest that exosome-associated HOTAIR may influence tumor progression-related processes and osteoclast-associated events relevant to bone metastatic progression. Furthermore, the Feiyanning formula (FYN) demonstrated inhibitory effects on tumor growth and metastasis-related phenotypes in experimental models.
circ-FSCN1 affects ferroptosis and cell viability in NSCLC via the miR-506-3p/SLC7A1 pathway.
Yu W, Liu J, Jin M … +2 more , Huang G, Huang Q
Transl Oncol · 2026 Jul · PMID 42107319 · Full text
circRNA is known to have regulatory functions across different cancers. Nevertheless, its regulatory functions in non-small cell lung cancer (NSCLC) are unknown. The present investigation aimed to research circ-FSCN1 exp...
circRNA is known to have regulatory functions across different cancers. Nevertheless, its regulatory functions in non-small cell lung cancer (NSCLC) are unknown. The present investigation aimed to research circ-FSCN1 expression in NSCLC cells and tissues employing high-throughput sequencing (HTS). NSCLC cells were investigated utilizing the CCK-8, EdU, and Transwell assays. Luciferase reporter assays were employed to verify circ-FSCN1 and its downstream target. Tumorigenesis and metastasis assays were performed to detect the role of circ-FSCN1 in NSCLC. Immunofluorescence was used to detect ROS deposition. The data indicated that the expression of hsa_circ_0004175 (circ-FSCN1) was elevated in NSCLC tissues and cells. The downregulation of circ-FSCN1 inhibited cellular migration and proliferation in the experiments. miR-506-3p downregulation or SLC7A1 overexpression reversed the suppression effects of sh-circ-FSCN1 on the proliferation and migration ability of H1299 and A549 cells. SLC7A1 overexpression reversed the inhibitory effects of miR-506-3p on the proliferation and migration ability of H1299 and A549 cells. The current investigation revealed that inhibiting miR-506-3p or overexpressing SLC7A1 reversed the enhancing effects of sh-circ-FSCN1 on ROS accumulation in H1299 and A549 cells. SLC7A1 overexpression reversed the enhancing effects of miR-506-3p on ROS accumulation in A549 and H1299 cells. Our investigation discovered that circ-FSCN1 affects ferroptosis and cell viability via the miR-506-3p/SLC7A1 pathway in NSCLC. circ-FSCN1 can function as a potential NSCLC diagnostic biomarker and therapy target.
CPT1B promotes acute myeloid leukemia progression via fatty acid oxidation-dependent metabolic reprogramming.
Cao R, Zhou LL, Liu Q … +3 more , Liu GE, Xu L, He H
Transl Oncol · 2026 Jul · PMID 42102499 · Full text
BACKGROUND: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with limited treatment options, especially in cases of relapse or refractory disease. Metabolic reprogramming, particularly fatty acid oxid...
BACKGROUND: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with limited treatment options, especially in cases of relapse or refractory disease. Metabolic reprogramming, particularly fatty acid oxidation (FAO), has emerged as a critical mechanism in AML progression. Carnitine palmitoyltransferase 1B (CPT1B), a rate-limiting enzyme in mitochondrial FAO, is highly expressed in metabolically active tissues, yet its role in AML remains poorly defined. METHODS: CPT1B expression was analyzed using TCGA datasets, patient samples, and AML cell lines. Functional studies employed CPT1B knockdown (shRNA) and overexpression (lentiviral) models in AML cell lines (THP-1, KG-1, HL-60, HEL). In vitro and in vivo effects were assessed via CCK-8, flow cytometry, western blot, ELISA, and xenograft models in immunodeficient mice. The FAO inhibitor Etomoxir was used to evaluate metabolic dependency. RESULTS: CPT1B was significantly overexpressed in AML tissues and cell lines compared to normal controls and correlated with poorer overall survival. CPT1B knockdown reduced proliferation, induced G0/G1 cell cycle arrest, and promoted apoptosis in AML cells. CPT1B silencing inhibited tumor growth and dissemination in vivo. Conversely, CPT1B overexpression enhanced FAO activity, increased lipid droplet accumulation, and upregulated PPARA, CPT1A, and ACOX1 expression. Treatment with Etomoxir reversed these effects, restoring apoptosis and inhibiting CPT1B-driven proliferation both in vitro and in mouse models. CONCLUSIONS: CPT1B acts as a key metabolic driver of AML progression through FAO-dependent lipid metabolic reprogramming. Its inhibition suppresses leukemic growth and improves survival outcomes, identifying the CPT1B-FAO axis as a promising therapeutic target and prognostic biomarker in AML.
Single-cell and spatial transcriptomic profiling of POU5F1 in Lung Adenocarcinoma: Dynamics, spatial niche, and prognosis via multi-algorithm ML.
Yu B, Zhang M, Zhu H … +3 more , Wu Z, Gao H, Bai Y
Transl Oncol · 2026 Jul · PMID 42097097 · Full text
BACKGROUND: POU5F1 (OCT4), a core regulator of pluripotency, plays an important role in tumor stemness and immune microenvironment remodeling, yet its systematic function and mechanisms in lung adenocarcinoma (LUAD) rema...
BACKGROUND: POU5F1 (OCT4), a core regulator of pluripotency, plays an important role in tumor stemness and immune microenvironment remodeling, yet its systematic function and mechanisms in lung adenocarcinoma (LUAD) remain incompletely elucidated. METHODS: This study integrated genetic causality inference, single‑cell and spatial transcriptomics, RNA velocity analysis, and multi‑algorithm machine learning to systematically investigate the role of POU5F1 in LUAD. Summary‑based Mendelian Randomization (SMR) was used to link GWAS with lung tissue eQTL data; single‑cell and spatial analyses characterized POU5F1 cell states and their interactions with cancer‑associated fibroblasts (CAFs); a machine‑learning prognostic model was constructed based on POU5F1‑related differentially expressed genes (LDEGs); and in vitro functional experiments were performed to validate its biological functions. RESULTS: POU5F1 was genetically associated with lung cancer risk and enriched in malignant, stem‑like cell clusters. RNA velocity indicated progressive activation along pseudotime trajectories. Spatial transcriptomics confirmed the co‑localization of POU5F1 tumor cells with CAFs. The LDEG‑based prognostic model showed excellent predictive performance (AUC > 0.9) and was correlated with immune suppression and targeted therapy response. Basic experiments further demonstrated that POU5F1 was specifically highly expressed in LUAD cell lines; knockdown of POU5F1 significantly inhibited cell proliferation, migration and invasion, and induced apoptosis; mechanistically, these effects involved regulation of the Bcl‑2/caspase‑3 apoptotic pathway, modulation of the epithelial‑mesenchymal transition (EMT) process mediated by E‑cadherin/Vimentin, and downregulation of the stemness factor Nanog. CONCLUSION: POU5F1 promotes LUAD progression by maintaining stemness, reprogramming CAFs, and shaping immune evasion, representing a promising biomarker and therapeutic target.
Targeting mir130b-IL-33-PD-L1 axis effectively inhibits esophageal squamous carcinoma progression.
Yue Y, Xian W, Yuan Y … +4 more , Wang X, Wu P, Sha X, Yue X
Transl Oncol · 2026 Jul · PMID 42092279 · Full text
We used an integrated approach combining molecular biology techniques, animal experiments, and clinical samples to elucidate the mechanistic basis of interleukin-33 (IL-33)-induced programmed death-ligand 1 (PD-L1) upreg...
We used an integrated approach combining molecular biology techniques, animal experiments, and clinical samples to elucidate the mechanistic basis of interleukin-33 (IL-33)-induced programmed death-ligand 1 (PD-L1) upregulation and its role in squamous cell carcinoma (ESCC) progression. Multi-omics analyses and clinical datasets identified that increased expression of IL-33 and its receptor in tumor tissues correlated with advanced stage and poor prognosis. IL-33 expression was associated with enhanced migration, invasion, and proliferation of tumor cells, and these effects were partly reversed by PD-L1 inhibition. Real-time PCR (qPCR) and functional assays in ESCC cell lines demonstrated that microRNA-130b-3p suppressed tumor progression by downregulating RUNX3, a transcriptional activator of IL-33. Dual-luciferase reporter assays confirmed direct targeting of RUNX3 by microRNA-130b-3p In vivo, microRNA-130b-3p overexpression reduced tumor growth in xenograft models and decreased levels of IL-33, PD-L1, and proliferation markers. Conversely, microRNA knockdown promoted tumor progression. Immunohistochemical analysis showed co-expression of IL-33 and PD-L1 in tumor cells, and PD-L1 blockade diminished IL-33-induced anti-apoptotic effects. Data integration revealed significant co-expression of IL-33 and PD-L1 across cancer types, suggesting a broader regulatory role. These findings establish a mechanistic link between microRNA-130b-3p and immune checkpoint activation through IL-33 signaling. The study identifies IL-33 as an independent prognostic marker and a key driver of PD-L1 expression, providing a basis for dual-targeted therapeutic strategies.
Integrated bioinformatics and experimental validation identifies CLIC6 as a novel tumor suppressor regulating NF-κB signaling and immune microenvironment in nasopharyngeal carcinoma.
Chen Z, Li M, Gao P … +1 more , Zhao Y
Transl Oncol · 2026 Jul · PMID 42092278 · Full text
BACKGROUND: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy. Tumor-associated macrophages play a pivotal role in NPC development, but molecular mechanisms remain unclear. This study aimed to...
BACKGROUND: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy. Tumor-associated macrophages play a pivotal role in NPC development, but molecular mechanisms remain unclear. This study aimed to identify M1 macrophage-associated hub genes and investigate their biological functions in NPC via bioinformatics and experimental validation. METHODS: GSE12452 and GSE53819 datasets were integrated to assess immune cell infiltration using CIBERSORT. WGCNA identified gene modules correlated with M1 macrophages. Hub genes were identified by intersecting differentially expressed genes with module genes, followed by LASSO regression and clinical specimen validation. CCK-8, Transwell assays, and macrophage co-culture systems were used to evaluate CLIC6 effects on NPC cell proliferation, invasion, and M1 polarization. RNA-seq and Western blot were performed to explore downstream mechanisms, with rescue experiments using NF-κB activator or inhibitor. RESULTS: M1 macrophages were significantly enriched in NPC tissues and negatively correlated with cilia-related gene modules. Six hub genes (MUC16, MS4A8, MUC20, AMIGO1, PHYHD1, CLIC6) were identified, with CLIC6 showing significant downregulation in NPC tissues and cell lines and negative correlation with M1 macrophages. CLIC6 recombinant protein promoted NPC cell proliferation and invasion while inhibiting M1 polarization, whereas CLIC6 silencing produced opposite effects. Mechanistically, CLIC6 suppressed NF-κB signaling by inhibiting IκBα and p65 phosphorylation, confirmed by RNA-seq and Western blot. Functional rescue experiments demonstrated that NF-κB modulation reversed CLIC6-mediated effects. CONCLUSION: CLIC6 functions as a tumor suppressor in NPC by inhibiting NF-κB signaling, thereby regulating tumor cell proliferation, invasion, and macrophage polarization. The CLIC6-NF-κB axis represents a potential diagnostic biomarker and therapeutic target for NPC.
Mitochondrial RNA helicase DDX28 promotes cell cycle and DNA repair programs and shapes an immunosuppressive microenvironment in acute myeloid leukemia.
Wang Z, Liu Y, Guan X … +2 more , Ye M, Xu X
Transl Oncol · 2026 Jul · PMID 42092277 · Full text
Acute myeloid leukemia (AML) is a heterogeneous malignancy with frequent relapse, driven by intertwined alterations in mitochondrial function, cell cycle control, genome maintenance, and immune evasion. DDX28 is a mitoch...
Acute myeloid leukemia (AML) is a heterogeneous malignancy with frequent relapse, driven by intertwined alterations in mitochondrial function, cell cycle control, genome maintenance, and immune evasion. DDX28 is a mitochondrial DEAD-box RNA helicase required for mitoribosome assembly and mitochondrial translation, and has been implicated in bioenergetic regulation in other tumor contexts. Here, we profiled DDX28 expression across AML cohorts using integrated multi-omics resources and evaluated its associations with prognosis, immune microenvironment features, and predicted drug response. Functional annotation, pathway analysis, GSEA, and targeted in vitro assays were used to explore potential mechanisms. High DDX28 expression was associated with inferior survival and higher blast burden. Mechanistically, elevated DDX28 expression was linked to promoter hypomethylation and was positively correlated with the transcription factor THAP11. Transcriptomic signatures in the high DDX28 group were enriched for cell cycle progression and DNA damage repair programs, together with an immune-suppressive landscape characterized by increased regulatory T cells and M2 macrophage signatures. Single-cell RNA-seq analyses further showed DDX28 enrichment in malignant blasts and exhausted or proliferative T-cell states. Consistently, DDX28 knockdown by siRNA in HEL cells reduced proliferation and impaired migration and invasion. Although direct metabolic flux measurements were not performed, the mitochondrial localization of DDX28 and the enrichment of proliferation and repair programs support a model in which DDX28 couples mitochondrial translation with the biosynthetic and genome maintenance demands of rapidly cycling AML cells. Collectively, our findings identify DDX28 as a prognostic indicator and a candidate regulator of malignant and immune states in AML, with potential relevance to therapeutic response.
Clinical validation of PEA-driven Olink proteomic discovery: INPP1 and ARHGAP25 serum biomarkers improve early breast cancer diagnosis.
Huang J, Gao L, Glazutdinova L … +5 more , Ji X, Zhang J, Lu Y, Zhang S, Liu Y
Transl Oncol · 2026 Jul · PMID 42085780 · Full text
BACKGROUND: Breast cancer is the most common malignant tumor in women all over the world, accounting for 15% of all female cancer-related mortality. Due to the limited sensitivity of current serum biomarkers (such as CA1...
BACKGROUND: Breast cancer is the most common malignant tumor in women all over the world, accounting for 15% of all female cancer-related mortality. Due to the limited sensitivity of current serum biomarkers (such as CA15-3, CEA) and the invasiveness of imaging/biopsy methods, early detection of breast cancer is still challenging. The purpose of this study is to use Olink proteomics to identify new diagnostic markers of breast cancer and integrate them into a multi-protein diagnostic model to improve the accuracy of early detection. METHODS: Serum proteomic profiling was performed via Olink's proximity extension assay (PEA) in a discovery cohort (15 breast cancer patients vs. 16 healthy controls). Differentially expressed proteins were analyzed to construct a diagnostic model, which was validated in an independent cohort (111 breast cancer patients [56 early-stage, 55 late-stage] vs. 95 healthy controls). RESULTS: The combination of INPP1 (first reported as downregulated in breast cancer serum) and ARHGAP25 demonstrated high diagnostic accuracy, achieving AUCs of 0.8458 (discovery cohort) and 0.8506 (validation cohort). Notably, the model retained efficacy in early-stage detection (AUC = 0.7598). CONCLUSION: This study identifies a novel serum protein panel (INPP1/ARHGAP25) as a minimally invasive tool for breast cancer diagnosis, particularly valuable for early-stage screening. The findings underscore the potential of proteomics-driven biomarker discovery to address clinical unmet needs.
TMEM72 Inhibits the proliferation by promoting cellular senescence through the activation of the P38/MAPK signaling pathway in renal cell carcinoma.
Dai F, Wang H, Chu W … +8 more , Lin Y, He J, Wen H, Feng X, Liu X, Xu Z, Bi L, Lyu Z
Transl Oncol · 2026 Jul · PMID 42070504 · Full text
BACKGROUND: Renal cell carcinoma (RCC) is a highly heterogeneous malignancy lacking reliable prognostic biomarkers and effective therapeutic targets. TMEM72, a kidney-enriched protein, is dysregulated in RCC, yet its bio...
BACKGROUND: Renal cell carcinoma (RCC) is a highly heterogeneous malignancy lacking reliable prognostic biomarkers and effective therapeutic targets. TMEM72, a kidney-enriched protein, is dysregulated in RCC, yet its biological function and underlying mechanisms remain unclear. METHODS: Proteomic profiling of paired RCC and adjacent tissues was performed to identify differentially expressed proteins. TMEM72 expression and clinical relevance were validated using the TCGA-KIRC cohort and an independent patient cohort. Functional assays, including proliferation, cell cycle, and senescence analyses, were conducted in gain- and loss-of-function RCC models, and in vivo effects were evaluated using a xenograft model. RNA sequencing, single-cell analysis, and immune infiltration analysis were performed to explore underlying mechanisms. RESULTS: TMEM72 was significantly downregulated in RCC and its low expression was associated with poor prognosis. TMEM72 overexpression suppressed RCC cell proliferation and tumor growth, whereas its silencing promoted tumor progression. Mechanistically, TMEM72 induced G1/S cell cycle arrest and promoted cellular senescence. Further analyses revealed that TMEM72 activated the p38/MAPK signaling pathway, leading to enhanced phosphorylation of p38 and p53, while pharmacological inhibition of p38 partially reversed these effects. Immune microenvironment analysis showed that TMEM72 was predominantly expressed in epithelial and malignant cells and was positively associated with infiltration of anti-tumor immune cells, including M1 macrophages, monocytes, and NK cells, but negatively correlated with immunosuppressive populations such as regulatory T cells and M0 macrophages. CONCLUSIONS: TMEM72 suppresses RCC progression by promoting p38/MAPK-dependent cellular senescence and may contribute to tumor immune microenvironment remodeling, highlighting its potential as a prognostic biomarker and therapeutic target.
Multimodal strategies for diagnosing and treating thyroid cancer: Advances in basic and clinical research.
Zhao Y, Su Y, Wu Y … +3 more , Mourdi N, Ji Y, Wang Z
Transl Oncol · 2026 Jul · PMID 42070503 · Full text
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, and its incidence has been increasing recently. Although the 5-year survival rate for PTC remains stable, the prognosis for medullary thyroid c...
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, and its incidence has been increasing recently. Although the 5-year survival rate for PTC remains stable, the prognosis for medullary thyroid carcinoma (MTC) and the highly aggressive, rare anaplastic thyroid carcinoma (ATC) is less favorable, underscoring the need for improved risk assessment. Additionally, there are still no effective treatments for MTC and ATC, emphasizing the urgency of developing personalized therapies. In this context, creating more precise diagnostic and treatment methods is essential. This review highlights recent advances in innovative diagnostic and therapeutic technologies for thyroid cancer and compares them with traditional approaches. It particularly focuses on how combining various radionuclides with positron emission tomography-computed tomography (PET-CT) facilitates innovative diagnostic and treatment solutions. The review also explores optical imaging for early tumor detection and real-time therapy guidance, as well as nanotechnology's role in transforming light into heat and free radicals-driving progress in both medicine and nanomaterials science. Moreover, it discusses RNA-based therapies as a promising, emerging approach that broadens treatment options for patients with thyroid cancer. Additionally, the review introduces intraoperative fluorescence navigation technology, which can reduce surgical complications and effectively integrate diagnosis and treatment.
Radiotherapy and immunotherapy for advanced cancers: A meta-analysis of dose, sequencing, and survival patterns.
Cao XJ, He XY, Yang Y … +1 more , Zhu Q
Transl Oncol · 2026 Jul · PMID 42068676 · Full text
BACKGROUND: Combining radiotherapy (RT) with immune checkpoint inhibitors (ICIs) offers potential synergy through RT-induced immunogenic cell death and enhanced systemic immunity. However, optimal RT dose, fractionation,...
BACKGROUND: Combining radiotherapy (RT) with immune checkpoint inhibitors (ICIs) offers potential synergy through RT-induced immunogenic cell death and enhanced systemic immunity. However, optimal RT dose, fractionation, and sequencing with ICIs remain unresolved. This meta-analysis evaluates the impact of biologically effective dose (BED), treatment timing, and ICI agents on progression-free survival (PFS) and safety in advanced cancers. METHODS: A systematic search of PubMed, Embase, Web of Science, and Cochrane Library (2010-2024) identified 18 studies (727 patients). Pooled PFS and treatment-related adverse events (TRAEs) were analyzed using random-effects models. Subgroup analyses stratified outcomes by cancer type, RT regimen, BED (low: ≤50; moderate: 50-100; high: >100), treatment sequence (concurrent/sequential), and ICI agents. This study was registered on PROSPERO (CRD420251044176). RESULTS: The synthesis of PFS revealed extreme between study heterogeneity, with a wide 95% prediction interval ranging from 0.90 to 41.21 months. Despite this variance, reconstructed individual patient data suggested that moderate BED regimens between 50 and 100 showed a more favorable median PFS compared to low or high dose regimens. Concurrent administration of radiotherapy and immunotherapy demonstrated a longer reconstructed median PFS than sequential strategies. Furthermore, PD-1 and PD-L1 based regimens appeared to perform better than CTLA-4-only approaches. The pooled incidence of grade 3 or higher TRAEs was 0.22, indicating a manageable overall safety profile. CONCLUSION: This descriptive meta-analysis and reconstructed individual patient data synthesis provide hypothesis-generating insights into combined radioimmunotherapy. Concurrent administration of moderate BED radiotherapy with PD-1 and PD-L1 inhibitors suggests a plausible balance of efficacy and safety. However, extreme heterogeneity limits direct clinical application, underscoring the critical need for standardized dose protocols and rigorous sequencing in future randomized trials.
Eprenetapopt in combination with Palbociclib exerts synthetic lethality in mantle cell lymphoma.
Dong L, Zhang Y, Chen F … +7 more , Jiang W, Qian S, Song W, Yang S, Wu X, Li Z, Zhang M
Transl Oncol · 2026 Jul · PMID 42068675 · Full text
BACKGROUND: Mantle cell lymphoma (MCL) exhibits distinct biological characteristics and marked molecular heterogeneity, with TP53 mutations associated with particularly poor clinical outcomes. Eprenetapopt (APR-246), a f...
BACKGROUND: Mantle cell lymphoma (MCL) exhibits distinct biological characteristics and marked molecular heterogeneity, with TP53 mutations associated with particularly poor clinical outcomes. Eprenetapopt (APR-246), a first-in-class mutant p53 reactivator, has shown broad anticancer activity across various tumor types. Palbociclib (PD0332991), a CDK4/6 inhibitor, targets CyclinD1-CDK4/6 complexes to counteract aberrant cell cycle regulation. This project will further explore the anti-tumor efficacy and the potential mechanism of APR-246 combined with PD0332991 in MCL. METHODS: In vitro, through assessments of cell proliferation, apoptosis, ROS levels, comet assays, and measurements of DNA damage and apoptosis-related proteins, along with CDX models in vivo, collectively investigated the synergistic anti-tumor efficacy of APR-246 combined with PD0332991 in MCL. Subsequently, through RNA-seq, along with GO functional annotation, KEGG pathway and GSEA enrichment analyses, we were further elucidated the underlying mechanisms and this was confirmed by UHRF1 rescue or knockdown experiments. RESULTS: In vitro, we found that APR-246 combined with PD0332991 showed synergistic inhibiting cell proliferation, enhancing apoptosis, increasing ROS, and promoted DNA damage in mut/del p53 MCL cells. In vivo, we observed synergistic inhibiting tumor growth without significant toxicity in CDX models. For the mechanism, we further inferred that the APR-246 combined with PD0332991 may coordinate downregulation the expression of UHRF1 and BRCA1 to inhibits the homologous recombination (HR) repair pathway. CONCLUSION: These findings support a rational therapeutic strategy that exploits oxidative genomic instability and synthetic lethality via HR pathway disruption, offering a promising combination therapy for managing mut/delp53 MCL.
Prognostic value and therapeutic potential of the cuproptosis-related gene LOXL2 in thyroid cancer.
Liu Y, Zeng Y, Wu S … +9 more , Xu G, Hu L, Ning J, Wang Y, Tao M, Luo W, Hao J, Zheng X, Gao M
Transl Oncol · 2026 Jul · PMID 42068674 · Full text
BACKGROUND: Cuproptosis, a copper-dependent form of programmed cell death, has been implicated in the progression of various cancers. However, the role of LOXL2 - a cuproptosis-related gene (CRG) - and its prognostic val...
BACKGROUND: Cuproptosis, a copper-dependent form of programmed cell death, has been implicated in the progression of various cancers. However, the role of LOXL2 - a cuproptosis-related gene (CRG) - and its prognostic value in thyroid cancer (THCA) remain largely unexplored. METHODS: We systematically investigated the prognostic significance of CRGs in THCA through an integrative approach combining bioinformatics screening and experimental validation. Expression profiling of all identified CRGs was performed using The Cancer Genome Atlas (THCA cohort) to assess their transcriptional alterations and associations with patient prognosis. Pathway enrichment, immune infiltration, and drug sensitivity analyses were subsequently conducted to explore the functional relevance of these genes. CRGs exhibiting significant differential expression and prognostic correlation were selected for in vitro functional validation using EdU proliferation, CCK-8, and Transwell assays to elucidate the role of LOXL2 in THCA progression. Additionally, we evaluated the antitumor effects of cuproptosis inducers on THCA cells to explore the therapeutic potential of targeting cuproptosis. RESULTS: Systematic expression analysis identified four CRGs (MT1A, MT1F, LOXL2, and MT1M) that were significantly dysregulated in THCA tissues compared to normal counterparts. Based on the expression patterns of these four genes, THCA patients were stratified into low-risk and high-risk groups. Notably, the high-risk group exhibited significantly lower immune scores and poorer overall survival. Pathway analysis revealed alterations in glycerolipid metabolism and oxidative phosphorylation in the high-risk group. Among the four genes, LOXL2 showed the strongest correlation with THCA prognosis. Functional assays demonstrated that LOXL2 knockdown significantly suppressed THCA cell viability, proliferation, migration, and invasion. Importantly, treatment with cuproptosis activators exerted potent anticancer effects against THCA cells. CONCLUSIONS: Our study indicates that LOXL2 may serve as a potential biomarker for cuproptosis-related pathways and represents a potential therapeutic target in THCA. Furthermore, our findings suggest that pharmacologically targeting cuproptosis-related genes may provide a promising therapeutic strategy for the management of THCA.
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