Clinical & Translational Oncology[JOURNAL]
Sun
200 papers
A positive feedback loop between CDH11 and TGF-β signaling regulates migration and invasion of gastric cancer.
Yan Q, Yu S, Dong Y … +4 more , Qing S, Song Q, Yao Y, Li Y
Transl Oncol · 2026 Jul · PMID 42127732 · Full text
OBJECTIVE: To investigate the molecular functions and underlying mechanisms of cadherin 11 (CDH11) in the pathogenesis of advanced gastric cancer (GC), and to evaluate the therapeutic potential of targeting CDH11 and its...
OBJECTIVE: To investigate the molecular functions and underlying mechanisms of cadherin 11 (CDH11) in the pathogenesis of advanced gastric cancer (GC), and to evaluate the therapeutic potential of targeting CDH11 and its associated signaling pathways. METHODS: The clinicopathological significance of CDH11 in GC was analyzed using the TCGA database. Experiments were conducted to assess the impact of genetic variations on the function of GC cell lines. The therapeutic potential of targeting CDH11 was evaluated in vitro and in vivo. The clinical relevance of CDH11 expression was further validated. RESULTS: TCGA analysis showed that CDH11 was highly expressed in GC and served as an independent prognostic biomarker. High CDH11 expression was also associated with a potentially immunosuppressive tumor microenvironment (TME) in GC. Mechanistically, CDH11 promoted epithelial-mesenchymal transition (EMT) and GC progression by upregulating TGF-β1 and activating TGF-β signaling. Activated TGF-β signaling enhanced CDH11 transcription via the binding of the downstream transcription factor Snail2 to the CDH11 promoter, thereby forming a positive regulatory loop. The targeting of CDH11/TGF-β signaling significantly suppressed migration and invasion of GC in vitro and lung metastasis of GC in vivo. Clinically, CDH11 and Vimentin were highly expressed in GC, especially in the diffuse-type cases, and a positive correlation between them was also identified. In the clinical samples, CDH11 was positively correlated with M2 macrophage marker CD163 and immune checkpoint PD-L1. CONCLUSION: The present study identifies a novel positive feedback loop between CDH11 and TGF-β signaling, which critically regulates EMT, migration, invasion and metastasis of GC cells. The targeting of this axis may represent a promising therapeutic strategy for GC.
Single-cell RNA sequencing reveals immune microenvironment heterogeneity in BRCA1-mutated and sporadic triple-negative breast cancer.
Sun Q, Zhong Y, Sun C
Transl Oncol · 2026 Jul · PMID 42119173 · Full text
Immune checkpoint blockade has shown benefit in some Triple-negative breast cancer (TNBC) patients, but responses are variable. BRCA1-mutated TNBC represents a biologically distinct subgroup, potentially differing in imm...
Immune checkpoint blockade has shown benefit in some Triple-negative breast cancer (TNBC) patients, but responses are variable. BRCA1-mutated TNBC represents a biologically distinct subgroup, potentially differing in immunogenicity and immunotherapy responsiveness. However, immune microenvironment differences between BRCA1-mutated and sporadic TNBC remain incompletely understood. By performing single-cell RNA sequencing analysis on sporadic TNBC and BRCA1 mutant TNBC, we assessed immune cell composition, transcriptional program, pathways, stemness, differentiation, and transcription factor regulatory networks. B cell and plasma cell subtypes were further explored using AUCell, CytoTRACE, Monocle2, and Slingshot. Compared to sporadic TNBC, BRCA1-mutated TNBC exhibited a distinct immune landscape with enriched naïve and memory B cells, while sporadic TNBC was dominated by terminally differentiated plasma cells, including IgA plasma cells. Functional enrichment analyses showed enhanced adaptive immune signaling, antigen presentation, and B cell receptor pathways in BRCA1-mutated TNBC, while sporadic TNBC had humoral effector and immunoregulatory programs. Trajectory and stemness analyses indicated enhanced cellular plasticity and decreased differentiation in B cells derived from BRCA1-mutated triple-negative breast cancer. Analysis of transcription factors revealed JUND and ETV1 in BRCA1-mutated TNBC, and MEIS1 and CEBPB in sporadic TNBC. Our findings underscore disparities in the immune ecosystem between BRCA1-mutated and spontaneous TNBC, indicating that the B cell-centric immunological milieu in BRCA1-mutated TNBC may offer a more advantageous setting for immunotherapy. Sporadic TNBC, by contrast, exhibits an immunological state characterized by plasma cells, which may restrict immune reactivation. These data indicate that B cell-based immunological stratification may guide precision immunotherapy approaches.
Feiyanning formula inhibits metastasis and differentiation of osteoclasts by targeting miR-328/NF-κB signaling axis via exosomal HOTAIR in lung cancer cells.
Zhang C, Liu Y, Lu Z … +13 more , Qin J, Yang L, Yin Q, Rao Z, Ji J, Chen K, Su W, Zhan X, Jin J, Ben W, Zhou Z, Huang X, Wang Z
Transl Oncol · 2026 Jul · PMID 42114285 · Full text
As one of the most lethal malignant tumors worldwide, the highly invasive and metastatic nature of lung cancer leads to a generally poor prognosis for patients. Among the complications associated with lung cancer, skelet...
As one of the most lethal malignant tumors worldwide, the highly invasive and metastatic nature of lung cancer leads to a generally poor prognosis for patients. Among the complications associated with lung cancer, skeletal-related events (SREs) resulting from bone metastases, including bone pain, pathological fractures, hypercalcemia, and spinal cord compression, significantly impair quality of life and reduce survival rates. The long non-coding RNA HOTAIR, which has been linked to various cancers, plays an unclear role in lung cancer bone metastasis and the regulation of the immune microenvironment. In this study, we investigated the expression of HOTAIR in non-small cell lung cancer (NSCLC) and its impact on the immune microenvironment using bioinformatics, microscopy, and functional assays. Our findings indicate that elevated HOTAIR expression is associated with poorer prognosis based on transcriptomic analyses. Bioinformatics validation in independent GEO datasets and clinical tissue samples also confirmed the prognostic value of HOTAIR in NSCLC bone metastasis subgroups. Mechanistically, HOTAIR expression was correlated with alterations in immune cell infiltration patterns, including reduced B-cell and CD8+ T-cell signatures, and was accompanied by increased NF-κB and ERBB pathway activity. These observations suggest that exosome-associated HOTAIR may influence tumor progression-related processes and osteoclast-associated events relevant to bone metastatic progression. Furthermore, the Feiyanning formula (FYN) demonstrated inhibitory effects on tumor growth and metastasis-related phenotypes in experimental models.
Targeting mir130b-IL-33-PD-L1 axis effectively inhibits esophageal squamous carcinoma progression.
Yue Y, Xian W, Yuan Y … +4 more , Wang X, Wu P, Sha X, Yue X
Transl Oncol · 2026 Jul · PMID 42092279 · Full text
We used an integrated approach combining molecular biology techniques, animal experiments, and clinical samples to elucidate the mechanistic basis of interleukin-33 (IL-33)-induced programmed death-ligand 1 (PD-L1) upreg...
We used an integrated approach combining molecular biology techniques, animal experiments, and clinical samples to elucidate the mechanistic basis of interleukin-33 (IL-33)-induced programmed death-ligand 1 (PD-L1) upregulation and its role in squamous cell carcinoma (ESCC) progression. Multi-omics analyses and clinical datasets identified that increased expression of IL-33 and its receptor in tumor tissues correlated with advanced stage and poor prognosis. IL-33 expression was associated with enhanced migration, invasion, and proliferation of tumor cells, and these effects were partly reversed by PD-L1 inhibition. Real-time PCR (qPCR) and functional assays in ESCC cell lines demonstrated that microRNA-130b-3p suppressed tumor progression by downregulating RUNX3, a transcriptional activator of IL-33. Dual-luciferase reporter assays confirmed direct targeting of RUNX3 by microRNA-130b-3p In vivo, microRNA-130b-3p overexpression reduced tumor growth in xenograft models and decreased levels of IL-33, PD-L1, and proliferation markers. Conversely, microRNA knockdown promoted tumor progression. Immunohistochemical analysis showed co-expression of IL-33 and PD-L1 in tumor cells, and PD-L1 blockade diminished IL-33-induced anti-apoptotic effects. Data integration revealed significant co-expression of IL-33 and PD-L1 across cancer types, suggesting a broader regulatory role. These findings establish a mechanistic link between microRNA-130b-3p and immune checkpoint activation through IL-33 signaling. The study identifies IL-33 as an independent prognostic marker and a key driver of PD-L1 expression, providing a basis for dual-targeted therapeutic strategies.
Integrated bioinformatics and experimental validation identifies CLIC6 as a novel tumor suppressor regulating NF-κB signaling and immune microenvironment in nasopharyngeal carcinoma.
Chen Z, Li M, Gao P … +1 more , Zhao Y
Transl Oncol · 2026 Jul · PMID 42092278 · Full text
BACKGROUND: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy. Tumor-associated macrophages play a pivotal role in NPC development, but molecular mechanisms remain unclear. This study aimed to...
BACKGROUND: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy. Tumor-associated macrophages play a pivotal role in NPC development, but molecular mechanisms remain unclear. This study aimed to identify M1 macrophage-associated hub genes and investigate their biological functions in NPC via bioinformatics and experimental validation. METHODS: GSE12452 and GSE53819 datasets were integrated to assess immune cell infiltration using CIBERSORT. WGCNA identified gene modules correlated with M1 macrophages. Hub genes were identified by intersecting differentially expressed genes with module genes, followed by LASSO regression and clinical specimen validation. CCK-8, Transwell assays, and macrophage co-culture systems were used to evaluate CLIC6 effects on NPC cell proliferation, invasion, and M1 polarization. RNA-seq and Western blot were performed to explore downstream mechanisms, with rescue experiments using NF-κB activator or inhibitor. RESULTS: M1 macrophages were significantly enriched in NPC tissues and negatively correlated with cilia-related gene modules. Six hub genes (MUC16, MS4A8, MUC20, AMIGO1, PHYHD1, CLIC6) were identified, with CLIC6 showing significant downregulation in NPC tissues and cell lines and negative correlation with M1 macrophages. CLIC6 recombinant protein promoted NPC cell proliferation and invasion while inhibiting M1 polarization, whereas CLIC6 silencing produced opposite effects. Mechanistically, CLIC6 suppressed NF-κB signaling by inhibiting IκBα and p65 phosphorylation, confirmed by RNA-seq and Western blot. Functional rescue experiments demonstrated that NF-κB modulation reversed CLIC6-mediated effects. CONCLUSION: CLIC6 functions as a tumor suppressor in NPC by inhibiting NF-κB signaling, thereby regulating tumor cell proliferation, invasion, and macrophage polarization. The CLIC6-NF-κB axis represents a potential diagnostic biomarker and therapeutic target for NPC.
Clinical validation of PEA-driven Olink proteomic discovery: INPP1 and ARHGAP25 serum biomarkers improve early breast cancer diagnosis.
Huang J, Gao L, Glazutdinova L … +5 more , Ji X, Zhang J, Lu Y, Zhang S, Liu Y
Transl Oncol · 2026 Jul · PMID 42085780 · Full text
BACKGROUND: Breast cancer is the most common malignant tumor in women all over the world, accounting for 15% of all female cancer-related mortality. Due to the limited sensitivity of current serum biomarkers (such as CA1...
BACKGROUND: Breast cancer is the most common malignant tumor in women all over the world, accounting for 15% of all female cancer-related mortality. Due to the limited sensitivity of current serum biomarkers (such as CA15-3, CEA) and the invasiveness of imaging/biopsy methods, early detection of breast cancer is still challenging. The purpose of this study is to use Olink proteomics to identify new diagnostic markers of breast cancer and integrate them into a multi-protein diagnostic model to improve the accuracy of early detection. METHODS: Serum proteomic profiling was performed via Olink's proximity extension assay (PEA) in a discovery cohort (15 breast cancer patients vs. 16 healthy controls). Differentially expressed proteins were analyzed to construct a diagnostic model, which was validated in an independent cohort (111 breast cancer patients [56 early-stage, 55 late-stage] vs. 95 healthy controls). RESULTS: The combination of INPP1 (first reported as downregulated in breast cancer serum) and ARHGAP25 demonstrated high diagnostic accuracy, achieving AUCs of 0.8458 (discovery cohort) and 0.8506 (validation cohort). Notably, the model retained efficacy in early-stage detection (AUC = 0.7598). CONCLUSION: This study identifies a novel serum protein panel (INPP1/ARHGAP25) as a minimally invasive tool for breast cancer diagnosis, particularly valuable for early-stage screening. The findings underscore the potential of proteomics-driven biomarker discovery to address clinical unmet needs.
TMEM72 Inhibits the proliferation by promoting cellular senescence through the activation of the P38/MAPK signaling pathway in renal cell carcinoma.
Dai F, Wang H, Chu W … +8 more , Lin Y, He J, Wen H, Feng X, Liu X, Xu Z, Bi L, Lyu Z
Transl Oncol · 2026 Jul · PMID 42070504 · Full text
BACKGROUND: Renal cell carcinoma (RCC) is a highly heterogeneous malignancy lacking reliable prognostic biomarkers and effective therapeutic targets. TMEM72, a kidney-enriched protein, is dysregulated in RCC, yet its bio...
BACKGROUND: Renal cell carcinoma (RCC) is a highly heterogeneous malignancy lacking reliable prognostic biomarkers and effective therapeutic targets. TMEM72, a kidney-enriched protein, is dysregulated in RCC, yet its biological function and underlying mechanisms remain unclear. METHODS: Proteomic profiling of paired RCC and adjacent tissues was performed to identify differentially expressed proteins. TMEM72 expression and clinical relevance were validated using the TCGA-KIRC cohort and an independent patient cohort. Functional assays, including proliferation, cell cycle, and senescence analyses, were conducted in gain- and loss-of-function RCC models, and in vivo effects were evaluated using a xenograft model. RNA sequencing, single-cell analysis, and immune infiltration analysis were performed to explore underlying mechanisms. RESULTS: TMEM72 was significantly downregulated in RCC and its low expression was associated with poor prognosis. TMEM72 overexpression suppressed RCC cell proliferation and tumor growth, whereas its silencing promoted tumor progression. Mechanistically, TMEM72 induced G1/S cell cycle arrest and promoted cellular senescence. Further analyses revealed that TMEM72 activated the p38/MAPK signaling pathway, leading to enhanced phosphorylation of p38 and p53, while pharmacological inhibition of p38 partially reversed these effects. Immune microenvironment analysis showed that TMEM72 was predominantly expressed in epithelial and malignant cells and was positively associated with infiltration of anti-tumor immune cells, including M1 macrophages, monocytes, and NK cells, but negatively correlated with immunosuppressive populations such as regulatory T cells and M0 macrophages. CONCLUSIONS: TMEM72 suppresses RCC progression by promoting p38/MAPK-dependent cellular senescence and may contribute to tumor immune microenvironment remodeling, highlighting its potential as a prognostic biomarker and therapeutic target.
Multimodal strategies for diagnosing and treating thyroid cancer: Advances in basic and clinical research.
Zhao Y, Su Y, Wu Y … +3 more , Mourdi N, Ji Y, Wang Z
Transl Oncol · 2026 Jul · PMID 42070503 · Full text
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, and its incidence has been increasing recently. Although the 5-year survival rate for PTC remains stable, the prognosis for medullary thyroid c...
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, and its incidence has been increasing recently. Although the 5-year survival rate for PTC remains stable, the prognosis for medullary thyroid carcinoma (MTC) and the highly aggressive, rare anaplastic thyroid carcinoma (ATC) is less favorable, underscoring the need for improved risk assessment. Additionally, there are still no effective treatments for MTC and ATC, emphasizing the urgency of developing personalized therapies. In this context, creating more precise diagnostic and treatment methods is essential. This review highlights recent advances in innovative diagnostic and therapeutic technologies for thyroid cancer and compares them with traditional approaches. It particularly focuses on how combining various radionuclides with positron emission tomography-computed tomography (PET-CT) facilitates innovative diagnostic and treatment solutions. The review also explores optical imaging for early tumor detection and real-time therapy guidance, as well as nanotechnology's role in transforming light into heat and free radicals-driving progress in both medicine and nanomaterials science. Moreover, it discusses RNA-based therapies as a promising, emerging approach that broadens treatment options for patients with thyroid cancer. Additionally, the review introduces intraoperative fluorescence navigation technology, which can reduce surgical complications and effectively integrate diagnosis and treatment.
Radiotherapy and immunotherapy for advanced cancers: A meta-analysis of dose, sequencing, and survival patterns.
Cao XJ, He XY, Yang Y … +1 more , Zhu Q
Transl Oncol · 2026 Jul · PMID 42068676 · Full text
BACKGROUND: Combining radiotherapy (RT) with immune checkpoint inhibitors (ICIs) offers potential synergy through RT-induced immunogenic cell death and enhanced systemic immunity. However, optimal RT dose, fractionation,...
BACKGROUND: Combining radiotherapy (RT) with immune checkpoint inhibitors (ICIs) offers potential synergy through RT-induced immunogenic cell death and enhanced systemic immunity. However, optimal RT dose, fractionation, and sequencing with ICIs remain unresolved. This meta-analysis evaluates the impact of biologically effective dose (BED), treatment timing, and ICI agents on progression-free survival (PFS) and safety in advanced cancers. METHODS: A systematic search of PubMed, Embase, Web of Science, and Cochrane Library (2010-2024) identified 18 studies (727 patients). Pooled PFS and treatment-related adverse events (TRAEs) were analyzed using random-effects models. Subgroup analyses stratified outcomes by cancer type, RT regimen, BED (low: ≤50; moderate: 50-100; high: >100), treatment sequence (concurrent/sequential), and ICI agents. This study was registered on PROSPERO (CRD420251044176). RESULTS: The synthesis of PFS revealed extreme between study heterogeneity, with a wide 95% prediction interval ranging from 0.90 to 41.21 months. Despite this variance, reconstructed individual patient data suggested that moderate BED regimens between 50 and 100 showed a more favorable median PFS compared to low or high dose regimens. Concurrent administration of radiotherapy and immunotherapy demonstrated a longer reconstructed median PFS than sequential strategies. Furthermore, PD-1 and PD-L1 based regimens appeared to perform better than CTLA-4-only approaches. The pooled incidence of grade 3 or higher TRAEs was 0.22, indicating a manageable overall safety profile. CONCLUSION: This descriptive meta-analysis and reconstructed individual patient data synthesis provide hypothesis-generating insights into combined radioimmunotherapy. Concurrent administration of moderate BED radiotherapy with PD-1 and PD-L1 inhibitors suggests a plausible balance of efficacy and safety. However, extreme heterogeneity limits direct clinical application, underscoring the critical need for standardized dose protocols and rigorous sequencing in future randomized trials.
Eprenetapopt in combination with Palbociclib exerts synthetic lethality in mantle cell lymphoma.
Dong L, Zhang Y, Chen F … +7 more , Jiang W, Qian S, Song W, Yang S, Wu X, Li Z, Zhang M
Transl Oncol · 2026 Jul · PMID 42068675 · Full text
BACKGROUND: Mantle cell lymphoma (MCL) exhibits distinct biological characteristics and marked molecular heterogeneity, with TP53 mutations associated with particularly poor clinical outcomes. Eprenetapopt (APR-246), a f...
BACKGROUND: Mantle cell lymphoma (MCL) exhibits distinct biological characteristics and marked molecular heterogeneity, with TP53 mutations associated with particularly poor clinical outcomes. Eprenetapopt (APR-246), a first-in-class mutant p53 reactivator, has shown broad anticancer activity across various tumor types. Palbociclib (PD0332991), a CDK4/6 inhibitor, targets CyclinD1-CDK4/6 complexes to counteract aberrant cell cycle regulation. This project will further explore the anti-tumor efficacy and the potential mechanism of APR-246 combined with PD0332991 in MCL. METHODS: In vitro, through assessments of cell proliferation, apoptosis, ROS levels, comet assays, and measurements of DNA damage and apoptosis-related proteins, along with CDX models in vivo, collectively investigated the synergistic anti-tumor efficacy of APR-246 combined with PD0332991 in MCL. Subsequently, through RNA-seq, along with GO functional annotation, KEGG pathway and GSEA enrichment analyses, we were further elucidated the underlying mechanisms and this was confirmed by UHRF1 rescue or knockdown experiments. RESULTS: In vitro, we found that APR-246 combined with PD0332991 showed synergistic inhibiting cell proliferation, enhancing apoptosis, increasing ROS, and promoted DNA damage in mut/del p53 MCL cells. In vivo, we observed synergistic inhibiting tumor growth without significant toxicity in CDX models. For the mechanism, we further inferred that the APR-246 combined with PD0332991 may coordinate downregulation the expression of UHRF1 and BRCA1 to inhibits the homologous recombination (HR) repair pathway. CONCLUSION: These findings support a rational therapeutic strategy that exploits oxidative genomic instability and synthetic lethality via HR pathway disruption, offering a promising combination therapy for managing mut/delp53 MCL.
Prognostic value and therapeutic potential of the cuproptosis-related gene LOXL2 in thyroid cancer.
Liu Y, Zeng Y, Wu S … +9 more , Xu G, Hu L, Ning J, Wang Y, Tao M, Luo W, Hao J, Zheng X, Gao M
Transl Oncol · 2026 Jul · PMID 42068674 · Full text
BACKGROUND: Cuproptosis, a copper-dependent form of programmed cell death, has been implicated in the progression of various cancers. However, the role of LOXL2 - a cuproptosis-related gene (CRG) - and its prognostic val...
BACKGROUND: Cuproptosis, a copper-dependent form of programmed cell death, has been implicated in the progression of various cancers. However, the role of LOXL2 - a cuproptosis-related gene (CRG) - and its prognostic value in thyroid cancer (THCA) remain largely unexplored. METHODS: We systematically investigated the prognostic significance of CRGs in THCA through an integrative approach combining bioinformatics screening and experimental validation. Expression profiling of all identified CRGs was performed using The Cancer Genome Atlas (THCA cohort) to assess their transcriptional alterations and associations with patient prognosis. Pathway enrichment, immune infiltration, and drug sensitivity analyses were subsequently conducted to explore the functional relevance of these genes. CRGs exhibiting significant differential expression and prognostic correlation were selected for in vitro functional validation using EdU proliferation, CCK-8, and Transwell assays to elucidate the role of LOXL2 in THCA progression. Additionally, we evaluated the antitumor effects of cuproptosis inducers on THCA cells to explore the therapeutic potential of targeting cuproptosis. RESULTS: Systematic expression analysis identified four CRGs (MT1A, MT1F, LOXL2, and MT1M) that were significantly dysregulated in THCA tissues compared to normal counterparts. Based on the expression patterns of these four genes, THCA patients were stratified into low-risk and high-risk groups. Notably, the high-risk group exhibited significantly lower immune scores and poorer overall survival. Pathway analysis revealed alterations in glycerolipid metabolism and oxidative phosphorylation in the high-risk group. Among the four genes, LOXL2 showed the strongest correlation with THCA prognosis. Functional assays demonstrated that LOXL2 knockdown significantly suppressed THCA cell viability, proliferation, migration, and invasion. Importantly, treatment with cuproptosis activators exerted potent anticancer effects against THCA cells. CONCLUSIONS: Our study indicates that LOXL2 may serve as a potential biomarker for cuproptosis-related pathways and represents a potential therapeutic target in THCA. Furthermore, our findings suggest that pharmacologically targeting cuproptosis-related genes may provide a promising therapeutic strategy for the management of THCA.
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.
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.
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.
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.
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.
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.
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