Translational Oncology[JOURNAL]
Sun
200 papers
Genetic architecture of multiple myeloma: From somatic alterations to germline susceptibility and clinical implications.
Carretero-Fernández M, Cabrera-Serrano AJ, Durán LR … +9 more , Ibañez M, Bonilla M, Mesa F, Gutiérrez-Bautista JF, Chahboun R, Reyes-Zurita FJ, Martínez-Lopez J, Collado R, Sainz J
Transl Oncol · 2026 Jul · PMID 42068673 · Full text
Multiple myeloma (MM) is best understood as a dynamically evolving genomic ecosystem shaped by inherited susceptibility, early oncogenic events, and continuous selective pressures. We propose an evolutionary genomics fra...
Multiple myeloma (MM) is best understood as a dynamically evolving genomic ecosystem shaped by inherited susceptibility, early oncogenic events, and continuous selective pressures. We propose an evolutionary genomics framework integrating germline risk, disease initiation, clonal diversification, and therapeutic adaptation into a unified model of MM biology. Polygenic risk burden, rare predisposing variants, and alterations in DNA repair and telomere pathways create a permissive background that influences precursor states and immune interactions. Primary cytogenetic events, particularly immunoglobulin heavy chain (IgH) translocations and hyperdiploidy, establish biologically distinct founding clones and constrain subsequent evolutionary trajectories. Disease progression is driven by secondary chromosomal alterations, copy number changes, MYC activation, TP53 loss, and structural rearrangements, promoting genomic instability and transcriptional plasticity. Longitudinal studies reveal branching clonal architectures shaped by treatment-driven selection. Integrating germline and somatic landscapes within an evolution-aware precision framework may improve risk stratification, anticipate high-risk trajectories, and support adaptive strategies to achieve more durable disease control. While polygenic risk scores (PRS) provide insight into inherited susceptibility, they are not yet clinically actionable for risk stratification or screening in MM and currently remain research tools. This framework provides a clinically oriented basis for applying genomic biomarkers to risk stratification, treatment selection, and longitudinal monitoring.
MT1G promotes the progression of ccRCC by suppressing ferroptosis through activation of the PI3K-AKT pathway.
Zhang L, Sun J, Ma Y … +2 more , Yan F, Huang Z
Transl Oncol · 2026 Jul · PMID 42068672 · Full text
Clear cell renal cell carcinoma (ccRCC) is the most common and clinically aggressive malignancy of the urinary system, characterized by dysregulated signaling pathways and resistance to ferroptosis. Metallothionein-1 G (...
Clear cell renal cell carcinoma (ccRCC) is the most common and clinically aggressive malignancy of the urinary system, characterized by dysregulated signaling pathways and resistance to ferroptosis. Metallothionein-1 G (MT1G) is generally downregulated in ccRCC; however, its elevated expression is paradoxically associated with poor prognosis, suggesting a pro-tumorigenic role. In this study, we integrated bioinformatics analyses with in vitro and in vivo experiments to investigate the biological function and underlying mechanisms of MT1G in ccRCC. Our results show that although MT1G is globally downregulated in ccRCC tissues, its expression positively correlates with PI3K-AKT pathway activity and ferroptosis suppression. Functional experiments revealed that MT1G knockdown inhibits proliferation, clonogenicity, and migration, while promoting ferroptosis and reducing PI3K-AKT activity. Conversely, MT1G overexpression or treatment with the PI3K agonist UCL-TRO-1938 rescues these phenotypes. In vivo xenograft models confirmed that MT1G silencing suppresses tumor growth, accompanied by reduced PI3K-AKT activity and downregulation of ferroptosis-suppressive markers, effects reversible by UCL-TRO-1938. Collectively, these findings demonstrate that MT1G promotes ccRCC progression by activating the PI3K-AKT pathway and suppressing ferroptosis, providing a mechanistic basis for its prognostic significance and potential as a therapeutic target.
Overexpression of NMNAT3 suppresses melanoma progression by reprogramming NAD⁺ metabolism.
Wu Y, Yu J
Transl Oncol · 2026 Jul · PMID 42068671 · Full text
BACKGROUND: Melanoma represents a highly aggressive and metastatic form of malignant skin cancer. that remains challenging to treat clinically. Tumor cells often reprogram nicotinamide adenine dinucleotide (NAD⁺) metabol...
BACKGROUND: Melanoma represents a highly aggressive and metastatic form of malignant skin cancer. that remains challenging to treat clinically. Tumor cells often reprogram nicotinamide adenine dinucleotide (NAD⁺) metabolism to meet the demands of rapid proliferation and metastasis, however, its function and mechanism in melanoma remain unclear. MATERIALS AND METHODS: Key NAD⁺ metabolism-related genes associated with melanoma were screened using bioinformatic analysis of public databases (GEO and TCGA). Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning approaches, further pinpointed NMNAT3 as a critical target for subsequent research. Confirmation of NMNAT3 expression on A375 melanoma cell line by qRT-PCR. Functional assays, including CCK-8 for proliferation, scratch wound for migration, and transwell for invasion, were employed to determine the roles of NMNAT3 in melanoma cells. Furthermore, an immune cell infiltration analysis was conducted to examine the association of NMNAT3 expression with the tumor immune microenvironment. RESULTS: Bioinformatic analyses indicated a downregulation of NMNAT3 in melanoma tissues and cell lines, demonstrating significant diagnostic potential. Moreover, Immunoanalysis shows important links between NMNAT3 expression and invasive levels of various immunologic types within the melanoma tumour microenvironment. Subsequent in vitro functional studies further showed that that NMNAT3 overexpression can significantly inhibit the malignant phenotype of melanoma cells. CONCLUSIONS: This study is the first to reveal the inhibitory role of NMNAT3 in melanoma growth. This study ensures an understanding of the theoretical principles of melanoma metabolic regulation and NMNAT3 treatment strategies.
Multi-scale evidence chain: Linking environmental BPA exposure to ovarian cancer through integrated omics and experimental models.
Luo Y, Mo S, Song P … +3 more , Meng K, Zhou J, Zou Y
Transl Oncol · 2026 Jul · PMID 42066461 · Full text
BACKGROUND: Ovarian cancer (OC) is a leading cause of female cancer mortality. Beyond genetic and reproductive risk factors, emerging evidence suggests bisphenol A (BPA), a widespread endocrine-disrupting chemical, may c...
BACKGROUND: Ovarian cancer (OC) is a leading cause of female cancer mortality. Beyond genetic and reproductive risk factors, emerging evidence suggests bisphenol A (BPA), a widespread endocrine-disrupting chemical, may contribute to ovarian carcinogenesis, though underlying mechanisms remain unclear. METHODS: We employed a multi-dimensional approach combining: (1) cross-sectional NHANES analysis (66 OC cases, 291 matched controls), (2) two-sample Mendelian randomization using GWAS data, (3) integrative bioinformatics (target prediction, nine GEO datasets, WGCNA, machine learning), (4) molecular docking/dynamics simulations, and (5) functional assays in SKOV3 cells. RESULTS: Urinary BPA levels were significantly elevated in OC patients (p < 0.05).Mendelian randomization suggested a positive association consistent with a potential causal effect (OR=1.25, p = 0.029). Five hub genes (LCN2, LIPA, NR3C1, NR3C2, PGR) were identified across algorithms, showing stable BPA binding in simulations. Single-cell analysis revealed enriched signatures in malignant epithelial cells (p = 0.009). Functional assays confirmed BPA promoted OC proliferation, migration, and invasion (p < 0.05). CONCLUSION: This integrated analysis provides multi-omic evidence supporting an association between BPA exposure and OC pathogenesis, with MR findings suggesting a potential causal relationship that requires independent replication, identifying five hub genes as potential biomarkers and therapeutic targets.
Growth hormone receptor antagonism improves tumoral chemo-immunotherapy response in a mouse model of lung cancer.
Ahmad A, Basu R, Fyffe C … +9 more , Geiger R, Walsh C, Brown FN, Bashir B, Alur AV, List E, Berryman D, Neggers SJCMM, Kopchick JJ
Transl Oncol · 2026 Jun · PMID 42061046 · Full text
Despite the clinical success of immune checkpoint inhibitors (ICIs), most patients with non-small cell lung cancer (NSCLC) fail to achieve durable responses due to intrinsic and acquired resistance. Growth hormone (GH) r...
Despite the clinical success of immune checkpoint inhibitors (ICIs), most patients with non-small cell lung cancer (NSCLC) fail to achieve durable responses due to intrinsic and acquired resistance. Growth hormone (GH) receptor (GHR) signaling has been implicated in tumor progression and therapy resistance, but its role in shaping anti-tumor immunity and chemo-immunotherapy response in NSCLC is unknown. To address this, syngeneic murine lung tumors were established in wild-type (WT) and GH antagonist transgenic (GHA) mice and treated with cisplatin, anti-PD-1 antibody, or their combination. Additionally, tumor growth was monitored longitudinally, while systemic and intratumoral insulin-like growth factor-1 (IGF-1) levels were quantified by ELISA. Tumor tissues were further analyzed by western blotting to assess immune checkpoint molecules, chemokine signaling components, and mediators of therapeutic resistance, and fibrotic remodeling was quantified using a hydroxyproline assay. High tumoral GHR expression was positively correlated with transcriptional signatures of therapy resistance, including ABC transporters, EMT markers, and ECM remodeling factors, and inversely associated with immune activation pathways. However, GHR antagonism in combination with cisplatin and anti-PD-1 therapy significantly suppressed tumor growth and enhanced therapeutic efficacy. Importantly, the combination of GHR blockade selectively increased PD-L1, PD-L2, and PD-1 expression, enhanced CXCL10-CXCR3 signaling, and downregulated the mediators of tumoral drug resistance and stromal remodeling. Therefore, we present the first indications that GHR signaling promotes immune suppression, therapy resistance, and fibrotic remodeling in NSCLC and support pharmacologic GHR antagonism as a novel strategy to sensitize tumors to chemo-immunotherapy.
Alcohol consumption and cancer progression: Mechanistic insights, immune dysregulation, and public health implications.
Deshpande RP, Tyagi A, Watabe K
Transl Oncol · 2026 Jun · PMID 42061045 · Full text
Alcohol consumption is a modifiable, dose‑dependent risk factor that accelerates cancer initiation, progression, and therapy resistance across breast, liver, colorectal, esophageal, and melanoma cancers. Alcohol metaboli...
Alcohol consumption is a modifiable, dose‑dependent risk factor that accelerates cancer initiation, progression, and therapy resistance across breast, liver, colorectal, esophageal, and melanoma cancers. Alcohol metabolism generates acetaldehyde, a genotoxic metabolite that induce DNA damage and impairs repair; drives oxidative stress, hormonal imbalance and promoting a tumor‑supportive microenvironment. These effects are amplified by obesity and insulin resistance, which heighten aggressiveness and blunt treatment response. Alcohol reshapes the tumor immune microenvironment (TIME) and undermines therapies, including immunotherapy. It impairs dendritic cell antigen presentation and co‑stimulation, limits CD4⁺/CD8⁺ priming, and expands immunosuppressive MDSCs and M2‑like TAMs that inhibit cytotoxic T cells and express checkpoint ligands. Concurrent cytokine shifts (TNFα, IL‑6), persistent ROS-NF‑κB signaling, and stromal/vascular remodeling promote immune exclusion and weaken responses to checkpoint blockade, targeted agents, and chemotherapy. Alcohol‑related gut dysbiosis is linked to ICB responsiveness-dampens antitumor immunity. Alcohol increases exosome biogenesis; circulating vesicles enriched in hepatocyte and inflammatory miRNAs (e.g., miR‑122, miR‑192) reprogram immune signaling and metastasis, forming a vesicular axis linking exposure to TIME dysfunction and resistance. Risk is synergistic with tobacco and worsens with aging as detoxification and DNA repair decline. Sex‑specific pharmacokinetics and composition confer vulnerability in women, while socioeconomic barriers delay diagnosis and care. Personalized prevention strategies that incorporate alcohol reduction, smoking cessation, and nutritional support, with emerging biomarkers such as exosomal miRNAs and alcohol‑related metabolites for early detection and risk stratification, are needed to mitigate alcohol‑related carcinogenesis, given the lack of definitive human evidence on alcohol's independent effects on immunotherapy and chemotherapy efficacy.
Anoctamin 5 as a protective factor in prostate cancer: Insights from WGCNA, machine learning, and experimental analysis, with a focus on the anoctamin family.
Wang JS, Shao LL, Yao D … +3 more , Sun DM, Lan JJ, Cong ZR
Transl Oncol · 2026 Jun · PMID 42055488 · Full text
OBJECTIVES: Prostate cancer (PCa) is a prevalent malignancy in males, triggered by multiple factors. This study aimed to identify PCa-specific key genes with clinical significance and clarify their roles in PCa progressi...
OBJECTIVES: Prostate cancer (PCa) is a prevalent malignancy in males, triggered by multiple factors. This study aimed to identify PCa-specific key genes with clinical significance and clarify their roles in PCa progression. METHODS: To screen PCa-specific key genes, a comprehensive analytical strategy was adopted by integrating weighted gene co-expression network analysis (WGCNA) for mining highly correlated important genes, Cox regression analysis for evaluating clinical relevance, and multiple machine learning techniques. Functional validation experiments were further conducted, including CCK-8 assay to assess cell proliferation, transwell assay, and wound healing assay to detect cell invasion and migration abilities after ANO5 overexpression in PCa cells. In addition, a model was constructed using machine learning to systematically clarify the role of ANO family genes in the occurrence of PCa. RESULTS: Anoctamin 5 (ANO5) was identified as a PCa-specific key gene through the integrated analytical approach. Clinical data analysis revealed that higher ANO5 expression was significantly correlated with favorable clinical status and longer survival time of PCa patients. Functional experiments confirmed this finding: the overexpression of ANO5 in PCa cells has an inhibitory effect on the behavior of tumor cells. Transwell and wound healing experiments further confirmed that ANO5 can inhibit the migration of PCa cells. CONCLUSION: ANO5 is a PCa-specific key gene that correlates with favorable clinical outcomes and regulates PCa cell invasion, suggesting its potential as a prognostic biomarker and therapeutic target. In comparison, the systematic exploration of ANO family genes enriches the understanding of PCa oncogenesis mechanisms.
Integrative multi-omics analysis identifies key ubiquitination regulators in prostate cancer.
Wei H, Gong C, Tan Z … +11 more , Yang E, Huang Y, An Y, Li H, Lv D, Yang C, Chen W, Wang H, Li S, Ding M, Wang J
Transl Oncol · 2026 Jun · PMID 42055487 · Full text
BACKGROUND: Ubiquitination plays a crucial role in tumor regulation, yet its specific functions in prostate cancer (PCa) remain incompletely understood. This study aimed to identify key genes associated with ubiquitinati...
BACKGROUND: Ubiquitination plays a crucial role in tumor regulation, yet its specific functions in prostate cancer (PCa) remain incompletely understood. This study aimed to identify key genes associated with ubiquitination processes in PCa and validate their roles across multiple biological levels. METHODS: We integrated single-cell RNA sequencing (scRNA-seq) data from the GEO database with summary-level genome-wide association study (GWAS) data. Through differential expression analysis, summary data-based Mendelian randomization (SMR), and single-cell trajectory analysis, ubiquitination-related genes (URGs) associated with PCa were screened. Validation was performed at both tissue and cellular levels: immunohistochemistry (IHC) on 30 PCa tissue samples stratified by Gleason grade (low-grade: ≤ 3 + 4; high-grade: ≥ 4 + 3), and Western blot (WB) along with quantitative PCR (qPCR) on PCa cell lines (22Rv1, LNCaP, PC-3) versus a normal prostate epithelial cell line (RWPE-1). Functional experiments including Transwell migration, wound healing, CCK-8 proliferation assays, and a cell line-derived xenograft (CDX) mouse model were conducted to validate the biological function of TRIM8. RESULTS: T lymphocytes and epithelial cells were the predominant cell types in the PCa microenvironment. SMR and MR analyses identified POLI and TRIM8 as key causal genes with significant protective associations against PCa (POLI: OR = 0.9385, P = 0.0046; TRIM8: OR = 0.8648, P < 0.001). Colocalization analyses supported their genetic regulatory roles. Molecular docking indicated a high binding affinity between selegiline hydrochloride and POLI (ΔG = -11.3kcal/mol). Experimental validations confirmed these findings: IHC revealed elevated POLI expression in high-grade tumors and higher TRIM8 expression in low-grade tumors. Consistently, WB and qPCR analyses demonstrated that POLI was significantly upregulated, while TRIM8 was downregulated, in PCa cell lines compared to normal controls. Functional assays further demonstrated that TRIM8 overexpression suppressed PC-3 cell migration, proliferation, and in vivo tumor growth, whereas TRIM8 knockdown exerted opposite effects, confirming its tumor-suppressive role. CONCLUSIONS: POLI and TRIM8 are key ubiquitination regulators with causal links to PCa pathogenesis, exhibiting distinct expression patterns correlated with tumor aggressiveness. Functional validation confirms TRIM8 as a tumor suppressor in PCa. These genes represent promising therapeutic targets, and the predicted interaction with selegiline hydrochloride highlights a potential drug-repurposing strategy.
Integrated mechanisms and clinical relevance of exercise driven remodeling of the tumor immune microenvironment.
Ye W, Wang J, Yang M … +5 more , Zhang X, Zeng S, Lei L, Xu Y, Li Y
Transl Oncol · 2026 Jun · PMID 42048753 · Full text
Immunotherapy has transformed cancer treatment, yet its overall efficacy remains constrained because the immune environment surrounding tumors is frequently maintained in a chronically suppressed state. A substantial bod...
Immunotherapy has transformed cancer treatment, yet its overall efficacy remains constrained because the immune environment surrounding tumors is frequently maintained in a chronically suppressed state. A substantial body of epidemiological and clinical evidence indicates that regular physical activity is consistently associated with reduced cancer incidence, lower recurrence rates, and prolonged survival. Despite these observations, the underlying biological basis has not been systematically clarified. Current data suggest that exercise modulates the immune environment through coordinated systemic and local pathways. At the systemic level, exercise mobilizes and activates immune cells while reducing chronic inflammation and physiological stress, thereby establishing conditions that favor immune responsiveness. At the local level, exercise improves blood supply, tissue architecture, and metabolic conditions within tumors and reshapes immune cell composition, collectively enhancing immune recognition and clearance of malignant cells. The concept of an immune plasticity window describes the capacity of the immune environment to transition from a suppressed to a responsive state and provides a unifying framework to integrate the diverse immunological effects of exercise. This framework helps explain interindividual variability in responses to exercise interventions and offers a conceptual basis for incorporating exercise into comprehensive cancer treatment strategies. By synthesizing clinical associations with mechanistic insights, this review emphasizes that exercise acts by globally improving the immune environment rather than targeting isolated pathways, supporting its potential role as an adjunct intervention to enhance therapeutic efficacy and long-term outcomes.
Core regulatory mechanisms of the PD-L1 axis and clinical strategies for immune escape and immunotherapy response in nasopharyngeal carcinoma.
Li H, Yang M, Li D … +1 more , Wang C
Transl Oncol · 2026 Jun · PMID 42035564 · Full text
The programmed death ligand 1 (PD-L1) axis serves as a pivotal pathway mediating tumor immune escape, with a unique and complex role in nasopharyngeal carcinoma (NPC). Recent advances in ICIs targeting the PD-1/PD-L1 pat...
The programmed death ligand 1 (PD-L1) axis serves as a pivotal pathway mediating tumor immune escape, with a unique and complex role in nasopharyngeal carcinoma (NPC). Recent advances in ICIs targeting the PD-1/PD-L1 pathway have significantly improved the prognosis of patients with recurrent or metastatic NPC. However, the clinical benefits exhibit substantial heterogeneity, underscoring the need to elucidate the underlying regulatory mechanisms. This review systematically summarizes the multilayered regulation of PD-L1 expression in NPC, encompassing genomic, transcriptional, epigenetic, and post-translational modifications. Special emphasis is placed on the influence of Epstein-Barr virus (EBV)-associated signaling, inflammatory cytokines, and therapeutic interventions on the dynamic modulation of PD-L1. Furthermore, the intrinsic relationship between dynamic PD-L1 expression changes and the efficacy and resistance mechanisms of ICIs is explored. Integrating the latest clinical trial data, we critically evaluate the progress and challenges of combining PD-1/PD-L1 inhibitors with chemotherapy, radiotherapy, and targeted therapies. Finally, we propose future directions for personalized immunotherapy strategies based on PD-L1 regulatory networks and biomarker development, aiming to optimize immune-based treatment paradigms for NPC and provide theoretical foundations and practical guidance for clinical management.
A macrophage co-expression signature enables robust prognostic prediction in glioblastoma.
Fang L, Li H, Ding C … +2 more , Feng L, Wang Y
Transl Oncol · 2026 Jun · PMID 42035563 · Full text
BACKGROUND: Glioblastoma (GBM) exhibits profound cellular heterogeneity and a highly immunosuppressive microenvironment in which tumor-associated macrophages represent a dominant immune component. However, how macrophage...
BACKGROUND: Glioblastoma (GBM) exhibits profound cellular heterogeneity and a highly immunosuppressive microenvironment in which tumor-associated macrophages represent a dominant immune component. However, how macrophage state-specific transcriptional programs and co-expression networks integrate to shape patient outcome and immunotherapy-related phenotypes remains insufficiently defined. METHOD: Single-cell RNA-seq data were integrated to resolve GBM cellular architecture and macrophage subpopulations. Macrophage regulatory and co-expression programs were inferred using R-SCENIC and hdWGCNA. Prognostically relevant genes were selected by integrating macrophage subcluster markers with key co-expression modules and survival screening in TCGA. A multi-algorithm machine learning framework was used to construct the Macrophage Co-expression-derived Risk Score (MCRS), which was validated in multiple independent cohorts. Immune landscapes, immunotherapy-related metrics, and pan-cancer analyses of SPP1 were systematically evaluated. In addition, an in silico virtual knockout analysis of SPP1 was performed to assess its potential downstream transcriptional effects in the GBM microenvironment. Finally, SPP1 was functionally validated in GBM cell lines. RESULTS: Macrophages segregated into distinct functional subpopulations with differential regulatory programs and prognostic relevance. hdWGCNA identified key macrophage modules linked to these states, enabling construction of the MCRS, which robustly stratified patient survival across TCGA, CGGA, and GEO cohorts. High MCRS was associated with coordinated immune-metabolic pathway activation, altered tumor purity, reduced immunogenicity, and increased immune escape potential. Pan-cancer analyses revealed widespread overexpression and adverse prognostic associations of SPP1. Virtual knockout of SPP1 induced distinct transcriptional changes enriched in immune-related biological processes and pathways, further supporting its involvement in macrophage-associated immune regulation. Experimental assays further showed that SPP1 promoted glioma cell proliferation, invasion, and clonogenicity. CONCLUSION: By integrating single-cell macrophage heterogeneity with co-expression network modeling, this study establishes MCRS as a robust prognostic and immunological stratifier in GBM and identifies SPP1 as a key macrophage-associated effector. Combined with in silico perturbation and experimental validation, these findings provide a biologically grounded framework for risk assessment and immunomodulatory targeting in GBM.
USP52 promotes clear cell renal carcinoma progression by deubiquitinating and stabilizing CORO6.
Wang X, Zhang N, Bu Y … +7 more , Zhang Y, Wang X, He X, Zhuang X, Zong Q, Zhou B, Luo G
Transl Oncol · 2026 Jun · PMID 42033890 · Full text
Clear cell renal carcinoma (ccRCC) is the most common type of kidney cancer. CORO6 functions as an oncogene in various malignancies, including ccRCC, but the mechanisms regulating its expression, particularly at the post...
Clear cell renal carcinoma (ccRCC) is the most common type of kidney cancer. CORO6 functions as an oncogene in various malignancies, including ccRCC, but the mechanisms regulating its expression, particularly at the post-translational level, remain poorly understood. Ubiquitin-specific proteases (USPs), the largest subfamily of deubiquitinases (DUBs), modulate the ubiquitination of target proteins and play crucial roles in numerous biological processes, such as ccRCC tumorigenesis. In this study, we screened USPs that potentially regulate CORO6 stability and identified USP52 as a key regulator that upregulates CORO6 expression. Bioinformatic analysis revealed that USP52 is overexpressed in ccRCC tissues and is negatively associated with patient prognosis. Similarly, USP52 expression was elevated in ccRCC cell lines, and its knockdown led to decreased CORO6 expression in these cells. In vitro experiments demonstrated that USP52 depletion reduced cell viability and proliferation, induced cell cycle arrest, increased apoptosis, and suppressed the migration and invasion of ccRCC cells. USP52 overexpression promotes the malignant phenotype of ccRCC cells. Mechanistically, USP52 interacts with CORO6, significantly decreasing its K48 ubiquitination and preventing its degradation in ccRCC cells. Notably, overexpression of CORO6 in USP52-deficient ccRCC cells effectively restored their malignant behaviors. Furthermore, using a xenograft mouse model of ccRCC, we found that USP52 deficiency impaired tumor growth in vivo, while CORO6 overexpression rescued the growth of USP52-deficient ccRCC cells. Collectively, these findings reveal that USP52 functions as an oncogene in ccRCC by deubiquitinating and stabilizing CORO6.
MUC16 promotes endometrial cancer progression and modulates sensitivity to lapatinib through the ESR1/PI3K/AKT axis.
Yu Y, Lv S, Li G … +2 more , Sun L, Su S
Transl Oncol · 2026 Jun · PMID 42030786 · Full text
PURPOSE: Endometrial cancer is one of the most common gynecological malignancies, and advanced disease remains associated with poor clinical outcomes. Mucin 16 (MUC16), a transmembrane glycoprotein frequently mutated in...
PURPOSE: Endometrial cancer is one of the most common gynecological malignancies, and advanced disease remains associated with poor clinical outcomes. Mucin 16 (MUC16), a transmembrane glycoprotein frequently mutated in multiple cancers, has been implicated in tumor progression. However, its functional role and molecular mechanism in endometrial cancer remain unclear. METHODS: Somatic mutation data from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) were analyzed to evaluate the association between MUC16 mutation and tumor mutation burden (TMB). Functional assays were performed in endometrial cancer cell lines. Protein interactions and ubiquitination were examined using co-immunoprecipitation and ubiquitination assays. Xenograft mouse models and drug sensitivity assays were used to evaluate tumor growth and response to targeted therapy. RESULTS: MUC16 is frequently mutated in endometrial cancer and its mutation status is associated with increased tumor mutation burden and improved overall survival in endometrial cancer patients. Functional experiments further demonstrated that MUC16 protein expression promotes tumor cell proliferation, migration, and invasion. Mechanistically, MUC16 interacted with estrogen receptor 1 (ESR1) and enhanced its stability by inhibiting ubiquitin-mediated degradation, thereby activating the PI3K/AKT signaling pathway. In addition, MUC16 knockdown significantly increased the sensitivity of endometrial cancer cells to the targeted drug lapatinib. CONCLUSION: These findings reveal that MUC16 promotes endometrial cancer progression through the ESR1/PI3K/AKT axis and highlight MUC16 as a potential prognostic biomarker and therapeutic target.
Toxicarioside H induces cytoprotective autophagy by hindering the progression of necroptosis in triple-negative breast cancer cells.
Xiong W, Tan GH, Chen H … +7 more , Chen MH, Wu RH, Dai SZ, Song T, He GS, Zheng WP, Huang FY
Transl Oncol · 2026 Jun · PMID 42030785 · Full text
Recent studies have shown that cardiac glycosides can induce protective autophagy, but the precise mechanism is unclear. Our research focused on Toxicarioside H (ToxH), a newly discovered cardiac glycoside, to explore it...
Recent studies have shown that cardiac glycosides can induce protective autophagy, but the precise mechanism is unclear. Our research focused on Toxicarioside H (ToxH), a newly discovered cardiac glycoside, to explore its ability to induce cytoprotective autophagy in triple-negative breast cancer (TNBC) cell lines and investigate the underlying mechanism. Cell growth and proliferation were measured using CCK-8 and EdU assays, while cell death was evaluated by flow cytometry and lactate dehydrogenase release assay. Autophagy and necroptosis markers were detected by Western blotting, and immunofluorescence was conducted for the autophagy marker LC3B and phosphorylated RIPK3 complex. Immunoprecipitation was used to detect the RIPK1/RIPK3 complex. Additionally, a mouse TNBC tumor model was established to assess the therapeutic effect of ToxH combined with CQ and the occurrence of autophagy and necroptosis. Our research showed that ToxH inhibited cell growth, increased cell death, and caused full autophagic flux in three TNBC cell lines. Co-treatment with CQ augmented ToxH's cytotoxicity both in vitro and in vivo. Autophagic degradation of the necroptosis-related proteins was observed in the TNBC cells treated with ToxH, as evidenced by the reduction of RIPK1/RIPK3 necrosomes and phosphorylated MLKL oligomers. This was restored by co-treatment with CQ. Autophagy and inhibition of necroptosis were also observed in TNBC tumor tissues. Our findings point to the conclusion that ToxH induces cytoprotective autophagy, leading to the breakdown of necrosomes and suppression of necroptosis in TNBC cells. Thus, a combination therapy involving ToxH and an autophagy inhibitor may be a potential treatment option for TNBC.
Comprehensive single-cell analysis reveals cellular heterogeneity and immune interactions in colorectal cancer.
Chi Z, Kong R, Wang S … +1 more , Qiu S
Transl Oncol · 2026 Jun · PMID 42024995 · Full text
Colorectal cancer (CRC) presents considerable therapeutic challenges due to its diverse cellular composition and intricate microenvironment. Our study utilized single-cell RNA sequencing (scRNA-seq) on CRC tissues, exami...
Colorectal cancer (CRC) presents considerable therapeutic challenges due to its diverse cellular composition and intricate microenvironment. Our study utilized single-cell RNA sequencing (scRNA-seq) on CRC tissues, examining 18,741 individual cells, which were grouped into six primary cell populations: epithelial, fibroblast, endothelial, T and NK, B, and myeloid. The epithelial cells exhibited notable variations in gene copy numbers. Within T_NK cells, we identified four distinct subsets. CytoTRACE analysis indicated that subtype C3 exhibited lower differentiation potential, whereas subtypes C0 and C1 showed higher differentiation potential. Consistently, Monocle pseudotime trajectory analysis positioned C3 cells at the terminal stage of differentiation, while C0 cells were enriched at the early stage of the developmental trajectory, suggesting functional heterogeneity among T/NK subpopulations. Through functional analyses with GSVA and ssGSEA, subtype C3 displayed the highest inflammation-associated activity scores. Further exploration of transcription factors defined three unique regulatory clusters among T_NK cells, illuminating their gene-regulation networks. We developed a prognostic signature using markers from subtype C3 T_NK cells combined with age-associated genes, revealing a significant correlation with patient survival outcomes. This prognostic model proved effective in categorizing CRC patients according to risk. Additionally, immune profiling employing ESTIMATE, CIBERSORT, and Xcell algorithms underscored the complexity of immune cell populations within CRC tumors. Analysis of tumor mutational burden (TMB) highlighted differential patterns between patient groups and its relationship to prognostic risk levels. Collectively, these insights provide a detailed perspective on CRC cell diversity and immune dynamics, supporting the advancement of targeted and personalized therapeutic interventions.
Exercise reshapes gut microbiota function to enhance cancer therapy.
Fang W, Wu Y, Yang Z … +6 more , Zheng H, Tang M, Xu Y, Chen R, Chen L, Ye X
Transl Oncol · 2026 Jun · PMID 42019280 · Full text
Marked interindividual variability in cancer treatment outcomes indicates that traditional strategies focused solely on direct tumor cell eradication are insufficient to explain real world clinical responses. Host respon...
Marked interindividual variability in cancer treatment outcomes indicates that traditional strategies focused solely on direct tumor cell eradication are insufficient to explain real world clinical responses. Host responsiveness to therapeutic stimuli has emerged as a critical determinant of efficacy. In recent years, the gut microbiota has been recognized as a central regulatory hub linking host immune and metabolic states with treatment outcomes. Through systemic modulation of immune activation thresholds, inflammatory tone, and tissue repair capacity, microbiota function participates deeply in shaping responses to immunotherapy, chemotherapy, and radiotherapy. Against the background of safety, stability, and personalization constraints associated with existing microbiota interventions, exercise has gained attention as a controllable endogenous physiological stimulus with long term feasibility. Regular physical activity reshapes the host metabolic milieu, strengthens intestinal barrier integrity, reduces basal systemic inflammation, and stabilizes immune homeostasis, thereby promoting a microbiota functional state that supports antitumor immunity. In this context, the host environment shifts from a passive background factor to an actively optimizable therapeutic variable. The regulatory axis formed by interactions between exercise and the gut microbiota provides a novel biological perspective for understanding treatment response heterogeneity across modalities and offers a unified functional rationale for enhancing immunotherapy responsiveness, improving chemotherapy tolerance, and facilitating radiotherapy associated tissue repair. Overall, integrating exercise into a host responsiveness centered therapeutic framework holds promise for amplifying treatment efficacy and improving long-term outcomes without altering existing oncologic regimens. With standardized study designs, refined functional assessment systems, and strengthened multidisciplinary collaboration, exercise mediated microbiota modulation is expected to progress from mechanistic exploration toward clinical implementation and become an integral component of comprehensive cancer therapy.
Deciphering IFN signaling in gastric cancer: A single-cell and bulk transcriptomic integration reveals CXCR4 as a key immunomodulator and prognostic determinant.
Song J, Wu F, Wang Y … +5 more , Chen Q, Zhang Y, Yu H, Chen Y, Jian J
Transl Oncol · 2026 Jun · PMID 42019279 · Full text
BACKGROUND: Gastric cancer (GC), a prevalent solid tumor, features a complex tumor microenvironment (TME) that influences immunotherapy responses. Leveraging single-cell RNA sequencing (scRNA-seq) and bulk transcriptomic...
BACKGROUND: Gastric cancer (GC), a prevalent solid tumor, features a complex tumor microenvironment (TME) that influences immunotherapy responses. Leveraging single-cell RNA sequencing (scRNA-seq) and bulk transcriptomics, we dissect the interplay between interferon (IFN) signaling and GC TME to identify actionable targets. METHODS: We analyzed bulk and scRNA-seq datasets. Gene Set Variation Analysis evaluated IFN pathway activity. The Scissor (single-cell identification of subpopulations with bulk sample phenotype correlation) algorithm and weighted gene co-expression network analysis identified survival-associated, IFN-correlated cellular subpopulations. Cell-cell communication within TME was mapped. A multi-gene prognostic signature was constructed and validated. qRT-PCR and Western blot detected marker gene expression. Flow cytometry assessed the proportion of macrophage polarization. CCK-8, Transwell, and scratch assays evaluated cell proliferation and migration. RESULTS: High IFN activity correlated with improved patient survival. scRNA-seq revealed macrophages and dendritic cells as primary IFN-activity hubs. Macrophages linked to poor prognosis (Scissor) exhibited the strongest IFN-γ-driven communication with tumor cells. We established a robust IFN-related prognostic model and pinpointed CXCR4 as a key adverse prognostic biomarker tightly coupled to IFN signaling. Low CXCR4 with high IFN activity defined a favorable prognostic profile. In cell experiments, CXCR4 deficiency in macrophages activated the IFN signaling pathway. Its overexpression reversed the inhibitory effect of IFN-γ treatment on malignant phenotype of AGS cells. CONCLUSIONS: This study elucidates IFN signaling network within the GC TME at single-cell resolution. We provide a prognostic model and identify CXCR4 as a promising therapeutic target, shedding mechanistic insights for refining immunotherapy strategies in GC.
Inflammatory biomarkers refine progression risk stratification in NSCLC patients with stable disease.
Kleinberger M, Laengle S, Berger JM … +11 more , Gottmann L, Sunder-Plassmann V, Korpan M, Solano Henao I, Fuerst J, Starzer AM, Berchtold L, Tomasich E, Preusser M, Furtner J, Berghoff AS
Transl Oncol · 2026 Jun · PMID 42013549 · Full text
INTRODUCTION: Early risk stratification of non-small cell lung cancer (NSCLC) patients with stable disease (SD) at first restaging is particularly challenging. We explored the prognostic value of clinical and inflammator...
INTRODUCTION: Early risk stratification of non-small cell lung cancer (NSCLC) patients with stable disease (SD) at first restaging is particularly challenging. We explored the prognostic value of clinical and inflammatory markers in this population. METHODS AND MATERIAL: We analysed a real-world cohort of prospectively enrolled advanced NSCLC patients undergoing systemic intravenous anticancer treatment in a palliative intent at the Medical University of Vienna between 2019 and 2024. Inflammatory blood markers were measured at baseline and first restaging, with blinded radiologic assessment. Uni- and multivariable logistic regression models evaluated associations with durable clinical benefit (DCB). RESULTS: Eighty NSCLC patients with SD at first restaging were included (median age 65 years, 50% female). Of those, 41 (51.3%) achieved DCB. Baseline characteristics were largely comparable. Patients with DCB had lower baseline neutrophil-to-lymphocyte and lymphocyte-to-leukocyte ratios. At first follow-up, CRP was lower and albumin higher in patients with DCB. In univariable analysis, lower follow-up albumin and higher LDH were associated with reduced odds of DCB. In multivariable models, PD-L1 positivity and follow-up albumin remained associated with DCB. The combined clinical-inflammatory model showed the highest apparent discriminative performance (AUC 0.766), compared to clinical-only (AUC 0.657) and inflammatory-only models (AUC 0.727), although the incremental improvement was modest. DISCUSSION: In patients with advanced NSCLC and SD at first restaging, inflammatory biomarkers were associated with additional discriminative information beyond clinical characteristics alone. A combined clinical-inflammatory model showed numerically higher discriminative performance; however, the improvement was modest.
Single-Cell sequencing investigation of endoplasmic reticulum stress-related genes in gastric cancer prognostic models and identification of NOX5 as a novel therapeutic target.
Fan Y, Liu F, Zuo H … +3 more , Chang K, Guo M, Liang Q
Transl Oncol · 2026 Jun · PMID 42013548 · Full text
BACKGROUND: Gastric cancer (GC) has a poor prognosis, and its pathogenesis remains incompletely understood. Endoplasmic reticulum stress (ERS) may influence GC progression, yet ERS-based prognostic models are lacking. We...
BACKGROUND: Gastric cancer (GC) has a poor prognosis, and its pathogenesis remains incompletely understood. Endoplasmic reticulum stress (ERS) may influence GC progression, yet ERS-based prognostic models are lacking. We aimed to develop an ERS-related prognostic signature using single-cell analysis and identify potential therapeutic targets. METHODS: Integrated analyses including single-cell RNA sequencing, cell‒cell communication, GSVA enrichment, and drug sensitivity inference were performed. A 14-gene prognostic model was constructed using Cox regression and LASSO, and validated via Kaplan-Meier and ROC curves. NOX5 function was assessed through in vitro proliferation and migration assays. RESULTS: The ERS signature outperformed clinicopathological parameters in predicting GC survival, with AUCs of 0.75, 0.71, and 0.64 for 1-, 3-, and 5-year OS, respectively. Patients were stratified into high- and low-risk groups with distinct immune checkpoint profiles. NOX5, the top risk gene (HR > 2.0), was upregulated in GC, and its knockdown significantly suppressed AGS and MKN-45 cell proliferation and migration (p < 0.01). CONCLUSION: The ERS-related signature is a promising independent prognostic and predictive biomarker for GC. NOX5 represents a novel potential therapeutic target.
Integrated multi-omics and machine learning highlight PTM-related genes as potential biomarkers in endometrial cancer.
Zhou X
Transl Oncol · 2026 Jun · PMID 42001686 · Full text
BACKGROUND: Endometrial cancer, the most common gynecological malignancy, represents about 5 % of all cancers in women, with rising incidence rates. Early-stage patients have favorable outcomes, but advanced or recurrent...
BACKGROUND: Endometrial cancer, the most common gynecological malignancy, represents about 5 % of all cancers in women, with rising incidence rates. Early-stage patients have favorable outcomes, but advanced or recurrent disease leads to poor prognosis and low survival. Current treatments primarily rely on surgery, underscoring the need for new therapeutic targets and biomarkers. Post-translational modifications are crucial in tumor development by regulating protein activity and stability, yet their role in endometrial cancer remains underexplored. METHODS: We integrated TCGA and GEO endometrial cancer data. PTM scores were calculated using AddModuleScore, and functional enrichment was conducted with clusterProfiler. Single-cell analysis was done with Seurat and Harmony, followed by UMAP and Louvain clustering. Machine learning techniques, including LASSO regression, SVM, and random forest, were applied to identify key genes. SHAP analysis evaluated their diagnostic contributions, and immune cell infiltration was analyzed using ssGSEA. MR on the FinnGen dataset assessed causal links between eQTLs of six genes and endometrial cancer. RESULTS: Differential expression analysis identified 2329 downregulated and 2910 upregulated genes in TCGA, and 2274 downregulated and 2545 upregulated genes in GEO. PTM analysis revealed key pathways, including protein deubiquitination and histone modification. Single-cell analysis identified 12 subpopulations. Six key genes were identified with high diagnostic accuracy. SHAP analysis highlighted UBE2C. MR analysis suggested high MYC expression as a risk factor (OR: 1.67, 95 % CI: 1.07-2.60, P = 0.024). CONCLUSION: This study provides valuable insights into the role of PTMs in endometrial cancer, identifying potential biomarkers for diagnosis and treatment.
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