Translational cancer research最新文献

For patients with inoperable locally advanced non-small cell lung cancer (LA-NSCLC), concurrent chemoradiotherapy followed by durvalumab consolidation is the current standard of care. However, local recurrence remains a predominant therapeutic obstacle. This review therefore aims to synthesize recent advancements in radiotherapy techniques, dose optimization, and immunotherapy integration to provide references for clinical practice and future research. This review synthesizes current literature to evaluate advancements in radiotherapy techniques, dose fractionation strategies, and their integration with immunotherapy. Intensity-modulated radiotherapy (IMRT) has become the standard technique, with long-term follow-up data confirming its survival benefits and safety. Advanced techniques including stereotactic body radiotherapy (SBRT) and particle therapy show potential for dose escalation but are limited by toxicity and a lack of high-level evidence. High-dose-rate brachytherapy (HDR-BT) demonstrates favorable local control with low toxicity and cost-effectiveness, though broader application awaits further validation. Regarding dose strategies, conventional dose escalation failed to improve survival, while hypofractionated radiotherapy shows promise in balancing efficacy and toxicity. The synergy with immunotherapy represents a new paradigm, with clinical trials actively exploring optimal combinations and leveraging radiotherapy's immunomodulatory potential. This review summarizes the current landscape and advancements in radiotherapy for LA-NSCLC. Future treatment strategies should develop personalized approaches based on multidisciplinary collaboration, utilizing precision radiotherapy to safely enhance treatment intensity, applying novel biomarkers to guide clinical decision-making, and optimizing combination strategies with immunotherapy.

Background: Lung cancer (LC) is the most prevalent and aggressive cancer worldwide. Immune checkpoint inhibitors (ICIs) can improve treatment outcomes, but a large number of patients still fail to respond to ICIs, suggesting the presence of additional synergistic inhibitory signaling pathways in the tumor microenvironment. Interleukin-20 receptor subunit beta (IL20RB), as a single transmembrane receptor protein, plays crucial roles in host defence, autoimmune responses, and tissue repair. This study aims to investigate the relationships of IL20RB with the prognosis and immune infiltration in LC patients.

Methods: We obtained clinical data and RNA sequencing data of 1,149 samples from The Cancer Genome Atlas (TCGA). Differential expression analysis identified a total of 2,739 differentially expressed genes (DEGs), including 36 differentially expressed immune-related genes (DEIRGs). Further least absolute shrinkage and selection operator (LASSO) regression analysis identified 16 DEIRGs as significant prognostic factors, with IL20RB emerging as a key target due to its high expression in LC. Functional enrichment analysis, prognosis-related gene feature verification, immune cell infiltration analysis and protein-protein interaction (PPI) network construction were performed for IL20RB. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect IL20RB expression levels in cell lines, and potential drugs were screened.

Results: Survival analysis revealed that a high IL20RB expression level was correlated with a poorer overall survival, suggesting its potential as a prognostic biomarker, with an area under the receiver operating characteristic curve (AUC) of 0.875. Functional enrichment analyses such as Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) indicated that IL20RB was involved in tumorigenesis and immunosuppressive pathways. Furthermore, IL20RB expression was positively correlated with multiple immune cells such as Th2 and natural killer (NK) CD56dim cells, and negatively correlated with eosinophils and Th17 cells. PPI networks constructed by STRING and GeneMANIA revealed the effects of IL20RB in immune receptor-mediated signaling activity and pathways. Pharmacological prediction analysis further identified that quercetin was a potential therapeutic agent targeting IL20RB.

Conclusions: IL20RB is highly expressed in LC patients, correlates with tumor immune infiltration, and serves as an independent prognostic factor, suggesting its potential as a biomarker for immunotherapy and prognosis assessment in LC.

Background: The orphan G protein-coupled receptor (GPCR) GPR137 is implicated in the proliferation of various tumor cells. However, its role and underlying mechanisms in medulloblastoma (MB), particularly the sonic hedgehog (SHH) subtype, remain unclear. This study aimed to investigate the function of GPR137 in SHH-MB and its potential regulation of ferroptosis via the Wnt/β-catenin pathway.

Methods: A GPR137-knockdown Daoy cell line was constructed using lentiviral shRNA. Cell proliferation, invasion, and colony formation were assessed using Cell Counting Kit-8 (CCK-8), wound healing, and colony formation assays, respectively. Ferroptosis was induced with erastin, and its inhibition was achieved with ferrostatin-1. Key ferroptosis markers, including lipid peroxidation products [malondialdehyde (MDA), 4-hydroxynonenal (4-HNE)], reactive oxygen species (ROS), glutathione (GSH) levels, and labile iron (Fe²⁺) were measured. The expression of ferroptosis-related proteins (GPX4, xCT) and Wnt/β-catenin pathway components was analyzed by western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Rescue experiments were performed by overexpressing β-catenin in GPR137-knockdown cells.

Results: GPR137 knockdown significantly inhibited Daoy cell proliferation, invasion, and colony formation. It synergized with erastin to aggravate ferroptosis, leading to increased cell death, elevated levels of MDA, 4-HNE, ROS, and Fe²⁺, alongside decreased GSH and downregulated GPX4 and xCT protein expression. These pro-ferroptotic effects were reversed by ferrostatin-1. Mechanistically, GPR137 depletion downregulated key mRNAs (β-catenin, c-jun, c-myc, cyclin D1, Axin2) and the protein level of β-catenin in the Wnt pathway. Crucially, β-catenin overexpression significantly alleviated the enhanced ferroptosis phenotype caused by GPR137 knockdown.

Conclusions: Our findings demonstrate that GPR137 deletion promotes ferroptosis in SHH-MB cells by inhibiting the Wnt/β-catenin signaling pathway. This reveals a novel regulatory axis in MB and suggests that targeting GPR137 could be a promising therapeutic strategy for SHH-MB.

Background: Endocrine-resistant estrogen receptor-positive (ER⁺) breast cancer often presents with an immune-cold phenotype, yet the upstream regulators driving immune evasion remain unclear. GNAL, a G-protein subunit involved in calcium signaling, has emerged as a potential player in modulating the tumor immune microenvironment, but its role in ER⁺ breast cancer has not been systematically investigated. This study aims to systematically investigate GNAL's biological functions, molecular mechanisms, and prognostic relevance in endocrine-resistant ER⁺ breast cancer, as well as its role in regulating the tumor immune microenvironment.

Methods: To elucidate the regulatory role of GNAL, we integrated summary-based Mendelian randomization (SMR), single-cell RNA sequencing, and spatial transcriptomics. Causal inference, cell-type mapping, and intercellular communication networks were analyzed, and a multi-omics prognostic model was constructed and validated across The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts.

Results: SMR analysis identified GNAL as a causal gene for ER⁺ breast cancer, with loss of expression was associated with increased recurrence risk. GNAL was specifically enriched in stromal stem-like subpopulations and decreased along with the stem cell differentiation trajectory. Spatial analyses revealed that GNAL⁺ stem-like cells recruited B cells via the MIF-CD74 signaling axis and established long-range communication with endothelial cells. A four-gene risk model (CD24, KDM3B, CEBPD, KRT14) predicted poor prognosis and was independent of Tumor (T), Node (N), and Metastasis (M) staging. High-risk tumors exhibited a 42% reduction in CD8⁺ T cell infiltration. Molecular docking identified stable hydrogen-bond interactions between GNAL and CEBPD.

Conclusions: GNAL regulates the spatiotemporal immune remodeling of ER⁺ breast cancer via calcium signaling and stem-like cell differentiation. The multi-omics risk model offers clinical prognostic value and highlights GNAL as a potential target for precision immunotherapy.

Background: Accurate identification of patients at risk of early death among young, non-metastatic gastric cancer cases at initial diagnosis may assist clinicians in optimizing treatment strategies. This study aimed to identify risk factors associated with early mortality in young patients with non-metastatic gastric cancer and to develop a clinically applicable nomogram for individualized risk prediction.

Methods: Eligible patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database and Sun Yat-sen University Cancer Center Gansu Hospital. Univariate and multivariate logistic regression analyses were conducted to identify independent predictors of early mortality. A nomogram was constructed based on the identified factors, and its performance was evaluated using the concordance index (C-index), receiver operating characteristic (ROC) curves, the Hosmer-Lemeshow test, and decision curve analysis (DCA) across training, internal validation, and external validation cohorts.

Results: The results revealed that T stage, N stage, radiotherapy, marital status, surgical treatment, tumor grade, and tumor size were independent predictors of early mortality. The nomogram demonstrated good discriminative ability, with C-index values of 0.748, 0.792, and 0.758 and area under the curve (AUC) of 0.81, 0.792, and 0.757 in the respective cohorts. Bootstrap resampling indicated good calibration, with low absolute prediction errors.

Conclusions: We have successfully developed effective nomograms to provide a reliable and practical tool for predicting early mortality and supporting clinical decision-making in young patients with non-metastatic gastric cancer.

Background: Gliomas account for the most frequent malignant neoplasms in the central nervous system (CNS). Though there have been developments in therapeutic approaches, the survival rate for most patients remains poor. This research aimed to explore the clinical importance and underlying mechanism of the atypical kinase right open reading frame kinase 1 (RIOK1) in the growth and proliferation of gliomas.

Methods: Differential expression analysis and survival analysis were assessed in public glioma datasets. The levels of RIOK1 protein expression in glioma tissues and non-tumor brain tissues were assessed via Western blot and immunohistochemical analysis. Cell Counting Kit-8 (CCK8) and 5-ethynyl-2'-deoxyuridine (EdU) assays were employed to evaluate glioma cell proliferation. Living cell imaging technology was applied to explore the impact of RIOK1 upregulation on glioma cell proliferative capacity under hypoxic conditions. Protein levels of selected protein kinase B/mammalian target of rapamycin (Akt/mTOR) pathway and apoptosis-related signaling members were evaluated using Western blot. Finally, glioma xenograft models were established to investigate the effect of RIOK1 on glioma tumorigenesis in vivo.

Results: We observed a significant downregulation of RIOK1 in isocitrate dehydrogenase (IDH) wild-type gliomas relative to IDH mutant-type gliomas. Compared to non-tumor brain tissues, glioma tissues exhibited a significant reduction in RIOK1 expression levels. Furthermore, overexpression of RIOK1 curbed the growth and proliferation of glioma cells, while downregulation of RIOK1 showed the opposite role. Hypoxia induced decreased expression of RIOK1, which was accompanied by elevated expression of hypoxia-inducible factor 1α (HIF-1α). Under hypoxic conditions, overexpression of RIOK1 inhibited the growth of glioma cells as well. Mechanistically, overexpression of RIOK1 diminished mTOR signaling pathway activity while boosting the activity of apoptosis-related signaling. In vivo, RIOK1 downregulation promotes glioma growth.

Conclusions: RIOK1 expression is lower in glioma tissues than in non-tumor brain tissues, and is particularly lower in IDH wild-type gliomas. RIOK1 functions as a suppressor of glioma cell survival and proliferation, possibly through mTOR pathway inhibition and apoptotic pathway activation.

Background and objective: Head and neck cancer (HNC) treatments, primarily involving radiotherapy (RT) and chemoradiotherapy (CRT), often result in significant acute and late toxicities that profoundly impact patients' quality of life. Although there are data supporting treatment de-escalation for human papillomavirus (HPV)-positive HNC patients, there is growing interest in applying similar principles to HPV-negative disease in order to maintain oncologic efficacy while reducing treatment-related morbidity. This review aims to synthesize and critically appraise the current evidence regarding dose and/or volume de escalation strategies specifically implemented in the treatment of HPV-negative HNC.

Methods: A search was conducted in SCOPUS and PubMed on June 30^th, 2025, including a time span from January 1^st, 2010 to June 29^th, 2025, using the following search criteria: (radiotherapy) AND ("head neck cancer" OR "head and neck cancer") AND (HPV-negative) AND ("de-escalation" OR "deescalation" OR "deintensification" OR "de-intensification" OR "reduced dose" OR "reduced volume"). All studies were screened for inclusion based on title and abstract, and the full texts were read and discussed by the research group in cases of uncertainty.

Key content and findings: Six studies were included in this review. For HPV-negative head and neck squamous cell carcinoma (HNSCC), neoadjuvant nivolumab combined with chemotherapy enabled response-stratified de-escalated CRT, achieving favorable survival outcomes with reduced acute toxicities. In nasopharyngeal carcinoma (NPC), reduced intensity modulated radiotherapy (IMRT) target volumes following induction chemotherapy (IC) demonstrated non-inferior locoregional control (LRC) and significantly improved long-term quality of life, mitigating late toxicities such as xerostomia and hearing loss. Regarding elective nodal irradiation (ENI), studies confirmed that lower radiation doses maintained LRC while leading to clinically meaningful reductions in toxicity without increasing isolated regional recurrences (RRs).

Conclusions: Dose and volume de-escalation appear feasible and beneficial in series that included HPV-negative HNSCC and NPC patients, maintaining oncologic efficacy while significantly reducing treatment-related toxicities. These findings expand the de-escalation paradigm beyond HPV-positive disease, offering a more tolerable therapeutic landscape.

Background: Breast cancer is a highly heterogeneous disease, and there is a continuing need for robust prognostic tools that can also inform therapeutic strategies. This study aimed to develop a novel prognostic signature for breast cancer by leveraging the multi-target philosophy of traditional Chinese medicine (TCM).

Methods: We systematically analyzed 221 TCM prescriptions for breast cancer to identify potential herb-related targets. A 20-gene herb-related risk score (HRS) was constructed using least absolute shrinkage and selection operator (LASSO) Cox regression in The Cancer Genome Atlas (TCGA) breast cancer cohort (n=1,097). The model's prognostic performance was validated in three independent cohorts: Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (n=1,466), GSE20685 (n=327), and GSE10886 (n=226). We further investigated the association of the HRS with the tumor immune microenvironment and potential drug sensitivity using bioinformatics algorithms.

Results: The HRS served as an independent prognostic factor for overall survival (OS) [TCGA: hazard ratio (HR) =2.03, 95% confidence interval (CI): 1.25-3.30, P=0.004; METABRIC: HR =1.82, 95% CI: 1.59-2.10, P<0.001]. Time-dependent receiver operating characteristic analysis demonstrated consistent prognostic discrimination, with an area under the curve (AUC) for 3-year OS of 0.709 (95% CI: 0.657-0.761) in the TCGA cohort. A high HRS was significantly associated with an immunosuppressive microenvironment and reduced predicted response to immune checkpoint blockade. Furthermore, the signature identified several compounds (e.g., sirolimus, temsirolimus) with potential heightened sensitivity in high-risk patients.

Conclusions: This study developed and validated a novel TCM-derived gene signature that reliably stratifies breast cancer patients into distinct risk groups and is independently prognostic. While its clinical utility requires extensive validation in prospective studies before it can inform patient management, this novel gene signature may serve as a potential tool for individualized risk assessment and prognosis prediction, while also generating compelling hypotheses for guiding immunotherapy and targeted therapy strategies, contributing to the ongoing exploration of precision oncology in breast cancer.

Background: Colorectal cancer (CRC) is one of the most common malignant tumors worldwide, characterized by difficulties in early diagnosis and frequent development of drug resistance to targeted therapies. Elucidating the molecular mechanisms of CRC pathogenesis and identifying novel molecular targets for early diagnosis and treatment are therefore of critical importance. Methyltransferase 16 (METTL16) plays crucial roles in CRC cell growth, development, and immune responses, making it a promising therapeutic target for CRC. Astaxanthin is a natural compound with numerous biological functions. This study aims to investigate the roles of METTL16 and astaxanthin in CRC, providing novel molecular targets and therapeutic directions for its treatment.

Methods: Expression of METTL16 and 5'-aminolevulinate synthase 1 (ALAS1) in CRC was analyzed using The Cancer Genome Atlas (TCGA) data. Changes in cell viability, proliferation, migration, and invasion following treatment of CRC cells with different concentrations of astaxanthin were evaluated using the Cell Counting Kit-8 (CCK-8), scratch healing assay, and Transwell assay. Western blot analysis was employed to detect changes in the expression of ferroptosis-related proteins. Additionally, kit-based assays were used to measure alterations in Fe²⁺ and malondialdehyde (MDA) levels.

Results: In vitro, astaxanthin demonstrates significant anti-tumor activity by inhibiting cell viability and proliferation. In vivo experiments using subcutaneous tumor-bearing mouse models further confirmed its ability to inhibit tumor growth and metastasis without apparent toxicity. Moreover, astaxanthin increases reactive oxygen species (ROS), MDA, and labile iron accumulation, thereby promoting ferroptosis, whereas METTL16 exhibits the opposite effect. Proteomics analysis further elucidated the relationship and mechanisms among METTL16, astaxanthin, and ferroptosis, revealing significant changes in several key proteins associated with ferroptosis-related pathways, mitochondrial energy metabolism, oxidative stress, and fatty acid metabolism.

Conclusions: This study demonstrates that astaxanthin inhibits CRC cell growth and delineates its relationship and mechanisms with METTL16 and ferroptosis, providing a new direction for CRC treatment.