Clinical & Translational Oncology[JOURNAL]
Sun
200 papers
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.
Transcriptomic and single-cell analyses reveal the prognostic value of ETV4 and its role in shaping the immune landscape of colorectal cancer.
Meng R, Wang S, She Z … +7 more , Wang H, Wu B, Qiao Y, Chen P, Nargerel, Yang X, Wang L
Transl Oncol · 2026 Jun · PMID 41997046 · Full text
BACKGROUND: Colorectal cancer (CRC) remains a major health threat with poor prognosis in advanced stages. The transcription factor ETV4 (ETS translocation variant 4) has been implicated in various cancers, but its specif...
BACKGROUND: Colorectal cancer (CRC) remains a major health threat with poor prognosis in advanced stages. The transcription factor ETV4 (ETS translocation variant 4) has been implicated in various cancers, but its specific role, prognostic value, and mechanisms in CRC, particularly concerning the tumor immune microenvironment, are not fully understood. METHODS: We performed a comprehensive analysis using transcriptomic data from The Cancer Genome Atlas (TCGA) and single-cell RNA sequencing data from the GEO database (GSE231559). Bioinformatic approaches included survival analysis, immune cell infiltration estimation via CIBERSORT, gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and single-cell clustering. Experimental validation was conducted on clinical CRC tissue samples and HCT-116 cells, employing flow cytometry, immunohistochemistry, quantitative real-time PCR (Q-PCR), and Western blot. RESULTS: In the TCGA cohort, ETV4 was significantly upregulated in 650 CRC tissues vs 51 adjacent normal tissues, with high expression linked to poorer overall survival in CRC patients.Immune infiltration analysis revealed correlations between ETV4 expression and specific immune cell subsets, notably macrophages. Flow cytometry and immunohistochemistry confirmed that high ETV4 expression was linked to increased polarization of immunosuppressive M2-type macrophages in the tumor microenvironment. Furthermore, bioinformatic GSVA and subsequent wet-lab experiments demonstrated that ETV4 is a downstream target gene of the WNT/β-catenin signaling pathway. Activation of this pathway upregulated ETV4 expression, while inhibition downregulated it, establishing a functional link. CONCLUSION: This integrative study reveals that ETV4 is a prognostic biomarker in CRC. It promotes tumor progression by reshaping the immunosuppressive microenvironment, particularly through inducing M2 macrophage polarization, and is regulated by the oncogenic WNT/β-catenin pathway. These findings suggest that ETV4 is expected to become a potential diagnostic biomarker and candidate therapeutic target for colorectal cancer, providing a novel direction for subsequent research on the diagnosis and treatment of CRC.
Clinical usefulness of polygenic risk scores in risk prediction models for lung cancer screening and lung nodule management.
Boumtje V, Li Z, Gaudreault N … +9 more , Saavedra Armero V, Boudreau DK, Plante S, Biardel S, Eslami A, Martel S, Thériault S, Joubert P, Bossé Y
Transl Oncol · 2026 Jun · PMID 41990546 · Full text
BACKGROUND: Lung cancer mortality decreases as a result of low-dose computed tomography (LDCT) screening, but suffers from low uptake and high false-positive rates. The impact of integrating genetic risk using a polygeni...
BACKGROUND: Lung cancer mortality decreases as a result of low-dose computed tomography (LDCT) screening, but suffers from low uptake and high false-positive rates. The impact of integrating genetic risk using a polygenic risk score (PRS) to optimize lung cancer screening remains underexplored. METHODS: We developed a genome-wide PRS and evaluated its performance in pre- and post-screening contexts. Screening eligibility was assessed using two UK Biobank (UKB) subsets: UKB (n = 8957; PLCOm2012norace risk ≥2%) and UKB (n = 74,024 meeting screening eligibility criteria). To evaluate nodule management, we used a cohort of 669 ever-smokers with PLCO ≥2% and Lung-RADS score ≥3, referred to as SYNERGIQC. Multivariable Cox models, time-dependent area under the curve (AUC), and decision curve analyses (DCA) evaluated association, discrimination, and clinical net benefit. RESULTS: In UKB, the PRS was associated with a hazard ratio (HR) of 1.18 per standard deviation. In UKB, PRS showed HR of 1.34. Adding PRS to the PLCOm2012 model improved discrimination (AUC: 0.707 vs 0.696; P = 6.85e[likelihood ratio test]) and correctly reclassified 9.2% of incident lung cancer cases. Six-year absolute risks stratified by PRS deciles indicate 3.1-fold increase in the top compared to the bottom decile. In SYNERGIQC, HR was 1.22. In this context, DCA indicated a modest net benefit for decision thresholds between 10% and 30%. CONCLUSION: PRS in lung cancer reveals context-dependent net benefit across studied populations. Although PRS adds limited value for determining screening eligibility, it may help reclassify borderline individuals and inform decisions regarding closer follow-up or invasive diagnostic procedures for high-risk screened groups.
Integrated spatial and single‑cell transcriptomics maps disulfidptosis in renal cell carcinoma and reveals PDLIM1 as a prognostic biomarker and potential therapeutic target.
Liu W, Liu X, Yi J … +13 more , Tang Z, Dai Z, Song J, Chen T, Wang J, Wang J, Jiang W, Jiang A, Wu Z, Tang L, Jin Y, Chen Y, Wang L
Transl Oncol · 2026 Jun · PMID 41985321 · Full text
BACKGROUND: Disulfidptosis is a regulated cell death program linked to redox stress, metabolism, and the actin cytoskeleton. Its organization in tissue and clinical relevance in renal cell carcinoma are not well defined....
BACKGROUND: Disulfidptosis is a regulated cell death program linked to redox stress, metabolism, and the actin cytoskeleton. Its organization in tissue and clinical relevance in renal cell carcinoma are not well defined. METHODS: We integrated spatial transcriptomics from six renal cancer sections with four single cell RNA sequencing cohorts. Disulfidptosis scores were computed, RCTD deconvolution and epithelial reclustering were used to localize subpopulations, and pathway enrichment and CytoTRACE assessed metabolism and stemness. External validation used TCGA-KIRC, KIRP and additional public datasets. Candidate genes were nominated by intersecting disulfidptosis, Cluster 3, and Epi_C5 signatures. PDLIM1 function was tested by sh-RNA in renal cancer cell lines with qPCR, proliferation, wound healing, and Transwell assays. RESULTS: Disulfidptosis showed strong intra heterogeneity. Spatial clusters 2, 3, and 6 were enriched, with Cluster 3 higher in tumors and linked to worse survival, and Cluster 6 context dependent yet adverse. Signals localized mainly to epithelial cells. Epithelial reclustering identified Epi_C5 with the highest disulfidptosis and Cluster 3 scores. Disulfidptosis-high cells were enriched for N glycan biosynthesis, purine and pyrimidine metabolism, oxidative phosphorylation, and nitrogen metabolism, with spatial overlap between nitrogen metabolism and disulfidptosis. Epi_C5 upregulated extracellular matrix programs, showed higher CytoTRACE, and associated with poor prognosis in both TCGA cohorts. Intersecting signatures nominated PDLIM1, which was tumor elevated and correlated with Epi_C5 and CytoTRACE. PDLIM1 knockdown reduced proliferation, and migration. CONCLUSIONS: We define a disulfidptosis‑associated epithelial malignant state in renal cancer and nominate PDLIM1 as a candidate node for patient stratification and therapeutic development.
Identification of MYC co-expression gene: POLR3G is associated with cell senescence, immunotherapy, chemotherapy responses, and clinical prognosis in bladder cancer patients.
Zhu L, Liu Y, Lan J … +5 more , Cai E, Sun D, Liu J, Zong L, Cong Z
Transl Oncol · 2026 Jun · PMID 41985320 · Full text
BACKGROUND: The MYC oncogene is a central driver of bladder cancer (BLCA) pathogenesis. However, the systematic role of its co-expressed gene network in BLCA progression, tumor microenvironment remodeling, and therapeuti...
BACKGROUND: The MYC oncogene is a central driver of bladder cancer (BLCA) pathogenesis. However, the systematic role of its co-expressed gene network in BLCA progression, tumor microenvironment remodeling, and therapeutic response remains largely unexplored. METHODS: Using the TCGA-BLCA dataset, we identified MYC co-expressed genes via the LinkedOmics platform. Consensus clustering was employed to define molecular subtypes based on this network. A prognostic signature was constructed using LASSO Cox regression. Immune infiltration was assessed with the xCell and TIP algorithms, and therapy responses were predicted via TIDE and drug sensitivity analysis. POLR3G's expression was validated in clinical samples using immunohistochemistry. RESULTS: Consensus clustering stratified BLCA patients into two distinct subtypes with significant survival differences, linked to NF-κB/IL-17/JAK-STAT and PPAR signaling pathways, respectively. A robust five-gene prognostic signature was developed. The high-risk group, characterized by an immunosuppressive microenvironment and elevated immune checkpoint expression, demonstrated poorer survival and predicted resistance to immune checkpoint blockade. Among the signature genes, POLR3G emerged as the most powerful independent prognostic factor. Furthermore, POLR3G expression was correlated with resistance to both chemotherapy and immunotherapy. Its upregulation in BLCA tissues was confirmed experimentally. CONCLUSION: Our study reveals that the MYC co-expression network is critical for BLCA heterogeneity. We established a novel prognostic signature with significant clinical utility for risk stratification and therapy guidance. POLR3G is highlighted as a pivotal oncogene associated with BLCA cell senescence and treatment resistance, thereby representing a promising new biomarker and therapeutic target.
PARP inhibitors target cellular energy metabolism: Mechanisms of action and clinical implications.
Li J, Mu D, Li J … +4 more , Lan M, Wu W, Zhang S, Dai Y
Transl Oncol · 2026 Jun · PMID 41967334 · Full text
Poly-ADP-ribose polymerase (PARP) is a multifunctional ribozyme that is involved in a variety of biological functions, including DNA repair, modulation of chromatin structure, RNA transcription, cell division, metabolism...
Poly-ADP-ribose polymerase (PARP) is a multifunctional ribozyme that is involved in a variety of biological functions, including DNA repair, modulation of chromatin structure, RNA transcription, cell division, metabolism, mitochondrial biology, oxidative stress biology, and cell death and differentiation. PARP inhibitors (PARPi) are a new class of targeted drugs widely used in the treatment of cancer with BRCA1/2 mutations and non-malignant diseases. Although PARPi has been known to affect the energy metabolism of cells, its exact effects and mechanisms on this process have not yet been fully understood. In this review article, we aim to provide a comprehensive overview of the current understanding of PARPi's effects on various physiological processes involving cellular energy metabolism, highlighting the importance of further exploring how the human body maintains the balance of energy metabolism during PARPi therapy. We also highlight the importance of future studies on the relationship between PARPi treatment and the depletion of NAD+ levels, the activation of PARP1, or the transition between different patterns of energy metabolism, to provide more insights into the safety and efficacy of PARPi in clinical practice.
NF-κB signaling in hepatocellular carcinoma: Mechanisms of tumor progression, immune evasion, and therapeutic resistance.
Yang P, Li X, Yang L … +4 more , Xiao N, Ren L, Ji M, Yang H
Transl Oncol · 2026 May · PMID 41956008 · Full text
Hepatocellular carcinoma (HCC) develops predominantly in the context of chronic liver inflammation and remains a leading cause of cancer-related mortality worldwide. Increasing evidence indicates that nuclear factor-κB (...
Hepatocellular carcinoma (HCC) develops predominantly in the context of chronic liver inflammation and remains a leading cause of cancer-related mortality worldwide. Increasing evidence indicates that nuclear factor-κB (NF-κB) signaling plays a central role in linking inflammatory stress to malignant progression in HCC. Beyond transient inflammatory activation, NF-κB is pathologically stabilized through alterations in proteostasis, kinase signaling, and loss of endogenous inhibitory circuits, resulting in sustained transcriptional activity. This persistent NF-κB signaling orchestrates multiple adaptive programs that collectively drive tumor growth, metabolic reprogramming, immune evasion, and resistance to therapy. In particular, NF-κB integrates proliferative and survival signaling with glycolytic dependence, redox homeostasis, epithelial-mesenchymal transition, and immunosuppressive remodeling of the tumor microenvironment. Moreover, NF-κB functions as a shared survival hub under therapeutic stress, promoting resistance to radiotherapy, chemotherapy, and ferroptosis-inducing strategies. Importantly, emerging evidence highlights the role of non-coding RNAs and tumor suppressors as endogenous brakes that restrain NF-κB activity, whose disruption contributes to its pathological fixation in HCC. In this review, we synthesize recent mechanistic and translational advances that redefine NF-κB as a central adaptive program in hepatocellular carcinoma. We further discuss the clinical implications of NF-κB signaling for tumor stratification and therapeutic intervention, emphasizing that effective targeting of HCC may require selective disruption of NF-κB-dependent adaptive modules rather than global pathway inhibition.
Integrative analysis of urinary microRNAs for prostate cancer detection: A proof-of-concept study.
Samani LA, Rahmani S, Kashi AH … +2 more , Ziaee SAM, Mowla SJ
Transl Oncol · 2026 May · PMID 41950670 · Full text
BACKGROUND: Liquid biopsies analyzing circulating nucleic acids offer a non‑invasive strategy for early detection, disease monitoring, and precision medicine. Among these, urinary microRNAs (miRNAs) have emerged as robus...
BACKGROUND: Liquid biopsies analyzing circulating nucleic acids offer a non‑invasive strategy for early detection, disease monitoring, and precision medicine. Among these, urinary microRNAs (miRNAs) have emerged as robust biomarkers owing to their stability and regulatory effects on gene expression and tumor progression. METHODS: A multi‑omics integrative analysis combining public microarray, bulk RNA‑seq, and single‑cell RNA‑seq datasets was performed to identify miRNAs differentially expressed between prostate cancer (PCa) patients and healthy controls. The diagnostic potential of these candidates was assessed using receiver operating characteristic (ROC) analysis and support vector machine (SVM) modeling. Validation was conducted through quantitative polymerase chain reaction (qPCR) on urine samples from 19 PCa and 7 benign prostatic hyperplasia (BPH) subjects. RESULTS: miR-23b-3p demonstrated consistent downregulation across transcriptomic datasets derived from urine, serum, and tissue. ROC and SVM analyses indicated strong diagnostic performance. Urinary qPCR validation yielded an area under the curve (AUC) of 0.79 (95% CI: 0.51-1.00), sensitivity of 0.73 (95% CI: 0.39-0.94), and specificity of 0.86 (95% CI: 0.42-1.00). CONCLUSIONS: The findings suggest that miR-23b-3p represents a promising complementary biomarker for non‑invasive PCa diagnosis. Further large‑scale validation integrating transcriptomic and clinical data is warranted to confirm its clinical applicability.
Circulating low-density neutrophils as biomarkers of resistance to first-line anti-PD-1/PD-L1 immunotherapy in non-small cell lung cancer.
Castro N, Labiano I, Martínez-Aguillo M … +17 more , Huerta AE, Morilla I, Teijeira L, Serrano D, Caseda I, Lecumberri A, Amat I, Zuazo M, Chocarro L, Blanco E, Escors D, Kochan G, Fernández Irigoyen J, Vera R, Calvo A, Alsina M, Arasanz H
Transl Oncol · 2026 May · PMID 41950668 · Full text
BACKGROUND: Immune checkpoint inhibitors (ICIs) have improved outcomes in advanced non-small cell lung cancer (NSCLC), however reliable predictive biomarkers are lacking. Our group previously reported an association betw...
BACKGROUND: Immune checkpoint inhibitors (ICIs) have improved outcomes in advanced non-small cell lung cancer (NSCLC), however reliable predictive biomarkers are lacking. Our group previously reported an association between high levels of circulating low-density neutrophils (LDNs) and resistance to ICI monotherapy. We present updated results, including a validation cohort, proteomic characterization of LDNs, and in vivo experiments exploring mechanisms of resistance. METHODS: NSCLC patients treated with first line ICI monotherapy (n=60) or combined with chemotherapy (CT+ICI) (n=60) were recruited. LDNs were quantified by flow cytometry and correlated with clinical outcomes. Phenotypes of LDNs and conventional neutrophils were characterised by flow cytometry and quantitative proteomics. Plasma cytokine measurements and in vivo experiments were conducted to assess the role of LDNs in ICI resistance. RESULTS: High baseline LDN levels were significantly associated with primary resistance to ICI monotherapy, with patients showing an overall response rate (ORR) of 17% vs 50% (p=0.04) and median progression free survival (mPFS) of 2.3 months vs 21.8 months (p < 0.001). No such association was seen in patients treated with CT+ICI, showing a LDN depletion in responders. LDNs exhibited an aged phenotype and distinct proteomic profile. Plasma from high-LDN patients showed elevated myeloid-expansion (M-CSF, IL1β) and inflammatory cytokines (CXCL9, IL-25). Depletion of Gr1+ population enhanced response to ICI and CT+ICI in the Lewis Lung Carcinoma (LLC) model with high LDNs. CONCLUSION: High baseline LDNs predict resistance to ICI monotherapy in NSCLC and combination with chemotherapy may overcome this resistance. Additional therapeutic strategies targeting LDNs could enhance immunotherapy efficacy.
Single-cell transcriptome analysis indicated that immune-related programmed cell death modification features could predict the clinical outcomes of patients with ovarian cancer.
Sun J, Jing L, Zhu X … +4 more , Yang H, Sun Y, Lu X, Liu Z
Transl Oncol · 2026 May · PMID 41946148 · Full text
BACKGROUND: Ovarian cancer (OV) is characterized by the highest mortality rate among gynecological malignancies. Suboptimal early diagnosis and ineffective prognostic prediction of OV contribute to poor survival outcomes...
BACKGROUND: Ovarian cancer (OV) is characterized by the highest mortality rate among gynecological malignancies. Suboptimal early diagnosis and ineffective prognostic prediction of OV contribute to poor survival outcomes for most patients. This study aimed to identify immune-related programmed cell death (IPCD) signatures and find the valuable biomarker for predicting OV prognosis. METHODS: All OV datasets were downloaded from public databases of TCGA, GEO and ICGC. Prognostic genes from IPCD-related differential genes were screened by univariate cox regression analysis. The construction of the IPCDS model was performed via 101 algorithm combinations. The prognostic performance of IPCDS model were examined by Kaplan-Meier analysis and timeROC curves. TIDE algorithm was used to predict the immune response of TCGA data. RESULTS: 88 IPCD-related prognostic genes were screened for modeling IPCDS. A significantly higher OS in low-IPCDS group was observed among most OV datasets than in high-IPCDS group. 2-, 3-, and 5-year timeROC results of each OV dataset revealed the excellent predictive value of IPCDS for OV, showing a relatively higher AUC after treated 2 years. The low IPCDS group had a higher TIDE value, while the no response group had a higher IPCDS value. In the pan-cancer immunotherapy dataset, patients in the low IPCDS group had a longer overall survival period and a significant immunotherapy effect. Besides, model gene PDGFRA were found to have predictive performance for OV. We validated the upregulation of PDGFRA and C-MYC in ovarian cancer tissues through Western blot and confirmed their co-localization and immunofluorescence analyses. CONCLUSION: Our study develops a novel prognostic model IPCDS for OV. IPCD-related gene PDGFRA serves as a prognosis factor play in predicting survival outcomes of OVs.
CD38 overexpression drives glioblastoma progression via L1CAM/ICAM1/JAK-STAT-Driven tumor microenvironment rewiring.
Norouzi S, Aulakh S
Transl Oncol · 2026 May · PMID 41946147 · Full text
BACKGROUND: Glioblastoma (GBM), a lethal primary brain malignancy, is characterized by dysregulated recruitment of tumor-associated macrophages and myeloid-derived suppressor cells, which promotes tumor growth, and enabl...
BACKGROUND: Glioblastoma (GBM), a lethal primary brain malignancy, is characterized by dysregulated recruitment of tumor-associated macrophages and myeloid-derived suppressor cells, which promotes tumor growth, and enables immune evasion. Given CD38's role as a multifunctional glycoprotein in hematological malignancies where it regulates immune cell trafficking, we hypothesized that CD38 overexpression in GBM modulates the tumor immune microenvironment. METHODS: We utilized the CRISPRa system to enhance CD38 expression in mouse syngeneic GL-261 cells. A murine GBM model was generated by intracranial injection of CD38-overexpressing (CD38-OE) GL-261 cells or CD38 wild-type (WT) or (parental)GL-261 cells into C57BL/6 mice. We utilized serial brain MRIs for tumor progression and assessed overall survival using Kaplan-Meier analysis. We performed multiplex flow cytometry and cytokine assays on brain tumor tissue. Data were analyzed using one-way ANOVA and unpaired t-tests. RESULTS: Median OS was significantly reduced in CD38-OE mice (26.5 days) versus CD38-WT (35.7 days; p < 0.0001; n = 11/group). Tumor size (in vivo) in CD38-OE vs CD38-WT at day 10 (8.44 mm³ vs. 2.16 mm³; p = 0.0004) and day 17 (34.75 mm³ vs. 8.51 mm³; p = 0.0048). Compared to CD38-WT, CD38-OE tumors showed increased infiltration of glioma-associated macrophages (GAMs) (8.43-fold increase; p < 0.0001), monocytic MDSCs (12.53-fold increase; p < 0.0002), polymorphonuclear MDSCs (15.66-fold increase; p < 0.0001), and T-regs (7.22-fold increase; p < 0.0001). Cytokine profiling indicated elevated CXCL10/IP-10, TIMP-1, and ICAM-1 in CD38-OE tumors. CONCLUSIONS: CD38 overexpression in GBM drives tumor progression by amplifying immunosuppressive TME remodeling, positioning CD38 as a compelling target for further clinical investigation, supported by preliminary efficacy of daratumumab (NCT04922723) in patients with GBM.
Proof-of-concept study of clinical use of blood-based MAVS biosensor in predicting immunotherapy response in SCLC patients.
Amato L, Tavoletta I, De Rosa C … +17 more , Seggio M, Arcadio F, Capaldo S, Ul Haq F, Tuccillo C, Esposito C, di Guida G, Iommelli F, De Rosa V, Reginelli A, Cappabianca S, Morgillo F, Ciardiello F, Nardone V, Cennamo N, Della Corte CM, Zeni L
Transl Oncol · 2026 May · PMID 41936750 · Full text
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with poor prognosis and limited benefit from immune checkpoint inhibitors (ICIs). Biomarker-driven patient stratification has been hindered by small bio...
Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with poor prognosis and limited benefit from immune checkpoint inhibitors (ICIs). Biomarker-driven patient stratification has been hindered by small biopsy samples, high tumor heterogeneity, and the limited predictive value of PD-L1 and tumor mutation burden. Mitochondrial antiviral-signaling protein (MAVS) has emerged as a potential immune activation marker, particularly in patients receiving DNA-damaging therapies. We report a proof-of-concept clinical study evaluating a surface plasmon resonance-plastic optical fiber (SPR‑POF) biosensor functionalized with anti-MAVS antibodies to detect the protein in serum from SCLC patients undergoing chemo-immunotherapy, with or without radiotherapy. The biosensor achieved a limit of detection of 0.13 nM in human diluted serum and demonstrated high selectivity against common serum proteins. In a cohort stratified as best responders (disease control >6 months) and non-responders (progressive disease as best response), MAVS levels measured in responders were on average tenfold higher than in non-responders, consistent with previous preclinical PBMC and western blot data. The SPR‑POF platform demonstrated portability, cost-effectiveness (estimated 5 USD/unit), and operational simplicity, highlighting its potential for point-of-care testing (POCT) applications. Although limited by small patient numbers, these findings support MAVS as a promising predictive biomarker in SCLC, warranting validation in larger prospective studies.
CCL2: A double-edged sword in neuroblastoma, with a critical role in MYCN-amplified tumors.
Jannot L, Gazeu A, Bendriss-Vermare N … +2 more , Pochon C, Sartelet H
Transl Oncol · 2026 May · PMID 41936749 · Full text
Neuroblastoma (NB) is the most common extracranial solid tumor in children, characterized by significant clinical heterogeneity and immune evasion. MYCN oncogene amplification is a major driver of tumor aggressiveness an...
Neuroblastoma (NB) is the most common extracranial solid tumor in children, characterized by significant clinical heterogeneity and immune evasion. MYCN oncogene amplification is a major driver of tumor aggressiveness and poor prognosis and is inversely correlated with immune infiltration in the tumor microenvironment (TME). Emerging evidence highlights the pivotal role of the chemokine C-C motif ligand 2 (CCL2) in modulating the immune landscape of NB. CCL2 influences the recruitment of various immune cells, including invariant natural killer T (iNKT) cells, dendritic cells (DCs), monocytes, macrophages, and regulatory T cells (Tregs), thereby shaping either pro- or anti-tumor responses depending on the context. MYCN-amplified tumors display reduced CCL2 expression, resulting in limited immune cell recruitment and the establishment of a "cold" TME with poor immune surveillance. In contrast, non-amplified tumors exhibit higher levels of CCL2, which attracts both anti-tumor immune cells such as DCs and macrophages, as well as pro-tumor populations including Tregs and tumor-associated macrophages (TAMs). These observations underscore the dual and context-dependent role of CCL2 in NB pathogenesis. Therapeutically, targeting the CCL2/CCR2 axis has shown promise in preclinical models, including approaches to enhance CAR-T cell trafficking and reduce TAM-mediated immunosuppression. Overall, CCL2 emerges as a central immunomodulatory molecule in NB, tightly linked to MYCN status and the composition of the TME. Understanding its complex biology is critical for the development of novel immunotherapies aimed at restoring effective anti-tumor immune responses, particularly in high-risk MYCN-amplified NB. Targeting the CCL2 axis represents a promising strategy to improve NB patient outcomes.
Unmasking FCGR2B as a high-grade serous ovarian cancer specific marker of immune suppression and tumor progression through multi-omics mining.
Zhou J, Zeng T, Ye M … +5 more , Li M, Wen L, Liu X, Zhang Z, Meng Y
Transl Oncol · 2026 May · PMID 41934917 · Full text
BACKGROUND: Epithelial ovarian cancer (EOC) encompasses five major histological subtypes with marked genetic, immunological, and clinical heterogeneity. While genome-wide association studies (GWAS) have identified subtyp...
BACKGROUND: Epithelial ovarian cancer (EOC) encompasses five major histological subtypes with marked genetic, immunological, and clinical heterogeneity. While genome-wide association studies (GWAS) have identified subtype-specific risk loci, a critical gap remains in understanding how plasma proteins influence immune-cell traits and contribute to EOC pathogenesis. METHODS: We integrated subtype-stratified GWAS data from two EOC cohorts with plasma proteomics and immune-cell traits to construct protein-immune-EOC regulatory landscapes using a three-stage Mendelian randomization framework. Single-cell RNA-seq and multiplex immunofluorescence were employed to delineate the cellular distribution and spatial context of causal proteins. Subsequent analyses characterized immune infiltration, macrophage polarization, and clinicopathological associations. Drug-gene correlations were used to identify potential therapeutic targets, and transcriptomic analyses were applied to delineate the underlying transcriptional landscape. RESULTS: We identified 20 subtype-specific protein-immune-EOC regulatory axes, with FCGR2B emerging as a causal plasma protein in immune regulation and high-grade serous ovarian cancer (HGSOC) progression. FCGR2B was highly expressed in tumor-associated macrophages and was associated with an M2-like polarization phenotype. Functional characterization revealed that FCGR2B was associated with shorter progression-free survival and an immunosuppressive tumor microenvironment. Transcriptomic analyses revealed altered NF-κB signaling upon FCGR2B knockdown, and drug-response data suggested a potential association between high FCGR2B expression and sensitivity to NF-κB inhibitors. CONCLUSIONS: These findings delineate subtype-specific genetically informed protein-immune regulatory landscapes in EOC and identify FCGR2B as a key immunoregulatory and prognostic biomarker in HGSOC, suggesting FCGR2B as a potential therapeutic vulnerability that warrants further investigation.
Synergistic effects through targeting the PI3K and IGFR pathways in treating lung cancer carrying activation alterations along the PI3K pathway.
Abd El-Salam M, Chen W, Tang Y … +9 more , Rao T, Kang X, Sun L, Han T, Chen P, Mossanen M, Cheng F, Yang C, Pan CX
Transl Oncol · 2026 May · PMID 41934916 · Full text
PURPOSE: Alterations in the PI3K/AKT pathway occur in over 60 % of lung squamous cell carcinoma and approximately 20 % of lung adenocarcinoma, driving tumor progression and therapeutic resistance. While PI3K-targeted the...
PURPOSE: Alterations in the PI3K/AKT pathway occur in over 60 % of lung squamous cell carcinoma and approximately 20 % of lung adenocarcinoma, driving tumor progression and therapeutic resistance. While PI3K-targeted therapies suppress proliferation in PIK3CA-mutant non-small cell lung cancer (NSCLC), their clinical impact is limited due to compensatory activation of insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R) signaling. This study aimed to determine whether dual blockade of PI3K and IR/IGF-1R signaling could overcome this adaptive resistance. METHODS: We assessed the effects of combining ceritinib, an ALK and IR/IGF-1R inhibitor, with a PI3K/AKT inhibitor in PIK3CA E545K-mutant H460 NSCLC cells. Functional assays included colony formation, wound healing, Matrigel invasion, and Western blot analyses. Therapeutic efficacy was further evaluated in a patient-derived xenograft (PDX) model of lung squamous cell carcinoma harboring the PIK3CA E545K mutation. Transcriptomic profiling using RNA-seq was conducted to identify resistance-associated pathways, and key findings were validated by qRT-PCR. RESULTS: Genetic ablation of PIK3CA markedly reduced proliferation. Dual inhibition of PI3K and IR/IGF-1R signaling resulted in strong synergistic anti-proliferative, anti-migratory, and anti-invasive effects in vitro. In the PDX model, the combination therapy significantly prolonged overall survival without additional systemic toxicity. Transcriptomic analysis revealed activation of the TNF-α/NF-κB axis as a potential mechanism of acquired resistance. CONCLUSION: Concurrent targeting of PI3K and IR/IGF-1R signaling effectively overcomes adaptive resistance in PIK3CA-mutant NSCLC, supporting the rationale for further clinical evaluation of this combined therapeutic strategy.
Supersensitive and robust disease monitoring in oropharyngeal cancer patients by circulating tumor HPV-DNA sequencing (ctHPV-DNAseq).
Pierik AS, Poell JB, Brink A … +14 more , Stigter-van Walsum M, Jansen F, de Bree R, Hardillo J, Langendijk JA, Takes RP, Lamers F, Verdonck-de Leeuw IM, Hendrickx JJ, Koppes SA, Rosing F, Waterboer T, Leemans CR, Brakenhoff RH
Transl Oncol · 2026 May · PMID 41921264 · Full text
BACKGROUND: Post-treatment disease monitoring of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) is challenging. Liquid biopsies could improve disease monitoring, but the variety in methods hampers clinical im...
BACKGROUND: Post-treatment disease monitoring of HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) is challenging. Liquid biopsies could improve disease monitoring, but the variety in methods hampers clinical implementation. In this study, target-enrichment sequencing to detect circulating tumor HPV DNA (ctHPV-DNA) was applied in liquid biopsies of HPV-positive OPSCC patients, and robust statistical readouts determined. Next, it was investigated whether longitudinal plasma monitoring could accurately diagnose residual and recurrent disease. METHODS: The target-enrichment panel included 29 cancer genes and high-risk HPV genomes. The assay was tested on plasma from 30 non-cancer controls and 33 patients with HPV-positive tumors, 15 of whom had residual or recurrent disease, and 18 who remained disease-free. Samples were analyzed from baseline to 24 months after treatment. RESULTS: By determining and applying robust statistical cut-off values, ctHPV-DNA could be detected in plasma of all patients with HPV-positive OPSCC at baseline, and was absent in plasma of all non-cancer controls. In OPSCC patients who remained disease-free, post-treatment plasma samples were negative for ctHPV-DNA. In contrast, ctHPV-DNA was detected in plasma of all OPSCC patients with recurrent disease to a year before clinical diagnosis. Cases suspect for residual disease in the neck, but with a necrotic metastasis without vital tumor after resection, tested correctly negative for ctHPV-DNA in plasma. CONCLUSIONS: Target-enrichment sequencing of plasma shows 100% accurate detection of ctHPV-DNA at baseline. Longitudinal monitoring enables early recurrence detection and correct diagnosis of non-vital residual disease. The data indicate that liquid biopsy could improve post-treatment follow-up in HPV-positive OPSCC patients.
SNHG7 interacts with PCBP2 to promote CDKN2A expression and modulate cuproptosis in colorectal cancer.
Chen Q, Song Q, Zhang H … +11 more , Lin Z, Shi Y, Chai Y, Fang X, Li N, Zheng Y, Yang Y, Wu X, Wang S, He C, Li M
Transl Oncol · 2026 May · PMID 41875809 · Full text
Colorectal cancer (CRC) ranks as the third most common malignancy worldwide. Cyclin dependent kinase inhibitor 2A (CDKN2A) is a key regulatory gene in the recently identified cell death pathway known as cuproptosis. The...
Colorectal cancer (CRC) ranks as the third most common malignancy worldwide. Cyclin dependent kinase inhibitor 2A (CDKN2A) is a key regulatory gene in the recently identified cell death pathway known as cuproptosis. The small nucleolar RNA host gene 7 (SNHG7) is an important and versatile molecule engaged in a variety of tumorigenic processes. Poly(rC)-binding protein 2 (PCBP2) is an RNA-binding protein that enhances RNA stability and is implicated in the progression of various tumors. However, the clinical role of cuproptosis-related SNHG7 in CRC largely remains unclear. We conducted cell culture and subcutaneous tumor formation experiments in nude mice, followed by qPCR, Western blotting, RNA immunoprecipitation, lactate production assays, gel electrophoresis, and immunohistochemistry on the corresponding tissues. Our results demonstrate that SNHG7 interacts with PCBP2 to enhance the expression of CDKN2A, thereby modulating cuproptosis and promoting glycolysis. These findings suggest that SNHG7 represents a promising therapeutic target for CRC.
Integrated single-cell and bulk transcriptomics reveals STAB1 as a novel therapeutic target for ovarian cancer.
Zhang Y, Chen J, Tang L … +3 more , Sun X, Yang L, Zhong Z
Transl Oncol · 2026 May · PMID 41865597 · Full text
The immunosuppressive tumor microenvironment (TME) and intrinsic heterogeneity of ovarian cancer (OC) are primary drivers of therapeutic resistance and mortality. To deconvolute these complex dynamics and identify robust...
The immunosuppressive tumor microenvironment (TME) and intrinsic heterogeneity of ovarian cancer (OC) are primary drivers of therapeutic resistance and mortality. To deconvolute these complex dynamics and identify robust therapeutic targets, this study employed an integrative strategy combining ensemble machine learning algorithms with high-resolution single-cell transcriptomics and experimental validation. Through dual-feature selection (LASSO and SVM-RFE) applied to multi-cohort bulk transcriptomic data, we identified Stabilin-1 (STAB1) as a top-ranked prognostic determinant. Crucially, single-cell analysis of the OC ecosystem redefined the cellular localization of STAB1, revealing its predominant enrichment in LYVE1+ perivascular-like M2 macrophages and a hyper-aggressive, EMT-active tumor subpopulation. Validating these in silico insights, in vitro loss-of-function assays confirmed that STAB1 silencing in OC cell lines (A2780 and SK-OV-3) significantly suppressed cell proliferation, colony formation, and invasion. Collectively, our findings support STAB1 as a pivotal "dual-checkpoint" molecule that bridges the immunosuppressive stroma and the malignant epithelium, highlighting its potential as a novel therapeutic target for dismantling the ovarian cancer ecosystem.
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