Clinical & Translational Oncology[JOURNAL]
Sun
200 papers
The SMAC-mimetic xevinapant differentially enhances cisplatin and immune checkpoint blockade efficacy in high-risk HPV-positive tumors.
Tsai TY, Kawabe M, Kaga AN … +3 more , Okamoto K, Myers JN, Osman AA
Transl Oncol · 2026 Aug · PMID 42235210 · Full text
OBJECTIVES: HPV-positive and HPV-negative head and neck squamous cell carcinomas (HNSCC) represent biologically distinct disease entities with divergent molecular and clinical features. Although inhibitors of apoptosis p...
OBJECTIVES: HPV-positive and HPV-negative head and neck squamous cell carcinomas (HNSCC) represent biologically distinct disease entities with divergent molecular and clinical features. Although inhibitors of apoptosis protein (IAP) antagonists have demonstrated radiosensitizing activity, recent phase III trials, including TrilynX, underscore the need for biologically informed patient selection and rational combination strategies. This study aimed to define context-dependent vulnerabilities of HPV-positive HNSCC to the SMAC mimetic xevinapant independent of radiotherapy. MATERIALS AND METHODS: HPV-positive and HPV-negative human HNSCC cell lines were assessed for sensitivity to xevinapant alone or combined with cisplatin using clonogenic survival, apoptosis assays, western blotting, and DNA damage analyses. Transcriptomic profiling was performed to identify treatment-associated signaling programs. In vivo efficacy was evaluated using orthotopic xenograft models treated with xevinapant and cisplatin. Immunomodulatory effects were examined in immunocompetent syngeneic mouse models expressing HPV16 E6/E7 following treatment with xevinapant and anti-PD-1 antibody. RESULTS: HPV-positive HNSCC models exhibited greater sensitivity to xevinapant monotherapy than HPV-negative counterparts, associated with rapid cIAP1 degradation, enhanced apoptosis, and disruption of the HPV E7-Rb-E2F axis. Xevinapant synergized with cisplatin, augmenting DNA damage and apoptotic signaling in vitro. Combination therapy suppressed tumor growth and prolonged survival in orthotopic xenografts without overt toxicity. In syngeneic models, IAP inhibition enhanced anti-PD-1 efficacy and suppressed tumor progression. Transcriptomic analyses revealed activation of type I and type II interferon signaling pathways. CONCLUSION: These findings identify a biologically defined vulnerability of HPV-positive HNSCC to IAP blockade and support xevinapant as an apoptosis-sensitizing and immunomodulatory agent rather than a uniform therapeutic intensifier.
RNA-Based and DNA-Based Next-Generation Sequencing of KIT and PDGFRA Mutations in Gastrointestinal Stromal Tumors: Analytical Performance and Epidemiologic Insights.
Jaladi S, Alvand S, Pitel BA … +9 more , Voss JS, Mopuri R, Fadra N, Sunder S, Atiq MA, Davila J, Gupta S, Kipp BR, Halling KC
Transl Oncol · 2026 Aug · PMID 42235209 · Full text
Mutations in the KIT and PDGFRA proto-oncogenes are key drivers in gastrointestinal stromal tumors (GIST) and guide targeted therapy. While DNA-based next-generation sequencing (NGS) is standard for mutation detection, R...
Mutations in the KIT and PDGFRA proto-oncogenes are key drivers in gastrointestinal stromal tumors (GIST) and guide targeted therapy. While DNA-based next-generation sequencing (NGS) is standard for mutation detection, RNA sequencing (RNA-Seq) may offer complementary advantages. This study evaluates RNA-Seq performance and presents molecular epidemiologic data from a large DNA-sequenced GIST cohort. RNA-Seq was performed on 24 GIST cases previously analyzed by DNA-based NGS (16 KIT mutants, 5 PDGFRA mutants, 3 wild-type) using the Agilent SureSelectXT RNA Direct Library Prep Kit and an in-house analysis pipeline. RNA-Seq was successful in 21 cases, identifying 13 of 14 KIT mutations and all PDGFRA mutations, including single nucleotide variants (SNV), insertions, and in-frame deletions (3-27 bp). One complex 45 bp deletion-insertion was not detected, though low-level evidence (<10% of reads) was present. Separately, DNA-based NGS results from 579 GIST cases were reviewed to assess mutation prevalence and clinicopathologic associations. Mutations were found in 83.2% of cases (403 KIT, 79 PDGFRA), with secondary KIT mutations in 6.0%. Mutation site correlated with tumor location and patient age; secondary mutations were more frequent in non-gastric tumors. RNA-Seq demonstrates high accuracy for detecting clinically relevant KIT and PDGFRA mutations and may complement DNA-based profiling. The DNA cohort provides broader context for mutation prevalence and patterns in clinical practice.
Advanced radiotherapy and systemic therapy in head and neck adenoid cystic carcinoma: Current progress and future integrated strategies.
Liu L, Zhou X, Li L … +2 more , Yang J, Tan M
Transl Oncol · 2026 Aug · PMID 42229289 · Full text
Head and neck adenoid cystic carcinoma (HNACC) remains a therapeutic challenge because of its infiltrative behavior, perineural tropism, and high propensity for distant metastasis. Although surgery combined with radiothe...
Head and neck adenoid cystic carcinoma (HNACC) remains a therapeutic challenge because of its infiltrative behavior, perineural tropism, and high propensity for distant metastasis. Although surgery combined with radiotherapy remains the standard local approach, treatment outcomes remain suboptimal in patients with unresectable tumors, advanced local disease, or anatomically complex lesions. Advances in radiotherapy, including MRI-guided radiotherapy, FLASH radiotherapy, and proton or carbon-ion therapy, are reshaping local treatment by improving dose precision, normal tissue sparing, and opportunities for treatment individualization. However, systemic therapy continues to face a therapeutic ceiling: conventional chemotherapy provides limited benefit, targeted therapy mainly achieves disease stabilization, and immunotherapy is constrained by the immune-cold microenvironment of HNACC. Emerging biomarkers and molecular targets, particularly NOTCH and TROP2(trophoblast cell-surface antigen 2), together with antibody-drug conjugates and other precision strategies, are beginning to expand the therapeutic landscape. Future management of HNACC will likely rely on integrated strategies that combine precision radiotherapy, biomarker-guided systemic therapy, and modulation of the tumor microenvironment to overcome both local and distant treatment failure.
Targeting tryptophan metabolism in breast cancer immunotherapy: Recent advances and future prospects.
Li G, Zhou H, Shen X … +2 more , Ying P, Lu H
Transl Oncol · 2026 Aug · PMID 42224955 · Full text
Breast cancer (BC), a leading cause of cancer-related mortality in women, is predominantly characterized as an immunologically "cold" malignancy. This recalcitrant nature is largely attributed to its profound metabolic l...
Breast cancer (BC), a leading cause of cancer-related mortality in women, is predominantly characterized as an immunologically "cold" malignancy. This recalcitrant nature is largely attributed to its profound metabolic landscape, which orchestrates a hostile tumor microenvironment (TME). Central to this metabolic subversion is the kynurenine (Kyn) pathway of tryptophan (Trp) catabolism. Driven by the rate-limiting enzymes indoleamine 2,3-dioxygenase 1/2 (IDO1/2) and tryptophan 2,3-dioxygenase (TDO2), this axis functions as a critical molecular rheostat that promotes immune evasion by depleting essential Trp and accumulating bioactive Kyn metabolites. This review provides a comprehensive analysis of the molecular basis by which the Trp-Kyn-aryl hydrocarbon receptor (AhR) signaling axis impairs T-cell effector function, induces regulatory T-cell (Treg) differentiation, and modulates the plasticity of myeloid-derived suppressor cells (MDSCs) specifically within the BC context. We critically evaluate the clinical trajectory of first-generation IDO1 inhibitors, analyzing the biochemical and compensatory mechanisms-such as TDO2 upregulation-that contributed to recent clinical setbacks. Furthermore, we highlight emerging strategies, including dual IDO1/TDO2 inhibitors, AhR antagonists, and nanomedicine-based delivery systems designed to overcome metabolic barriers. By emphasizing the integration of Trp-targeted agents with immune checkpoint blockade and other conventional therapies, we propose a framework for biomarker-driven patient stratification. Ultimately, we outline future directions to transition from "one-size-fits-all" approaches toward precision metabolic immunotherapy to unlock robust anti-tumor immunity in breast cancer.
Progesterone induces steroidome and lipidome remodeling in a BRCA-resembling mouse model of high-grade serous ovarian cancer.
Schwiebert EM, Vega-Herrera A, Botros A … +5 more , Moore SG, Gaul DA, Kim O, Kim J, Fernández FM
Transl Oncol · 2026 Aug · PMID 42224954 · Full text
Ovarian cancer (OC) is the deadliest gynecological disease in women, with high-grade serous ovarian cancer (HGSC) being its most common and lethal subtype. This disease accounts for 75% of OC cases and has a five-year su...
Ovarian cancer (OC) is the deadliest gynecological disease in women, with high-grade serous ovarian cancer (HGSC) being its most common and lethal subtype. This disease accounts for 75% of OC cases and has a five-year survival rate of only 32%, mainly due to diagnoses at an advanced stage. Inheriting a pathogenic BRCA1 or 2 mutation significantly increases the risk of developing HGSC. However, the early molecular processes that lead to this deadly subtype remain poorly understood. The ovarian hormone progesterone (P4) has been shown to induce metastatic HGSC in Dicer1-Pten double-knockout (DKO) mice, an animal model that develops this specific type of OC with molecular, histological, and clinical features similar to those of BRCA1/2 mutation carriers. To explore P4-induced metabolic changes before and after the onset of HGSC, we analyzed serum samples from DKO mice treated with P4 or mifepristone, an inhibitor of P4 signaling, at premalignant and early tumor stages. These samples underwent both targeted and non-targeted metabolomic analysis using ultra-high performance liquid chromatography-mass spectrometry. The non-targeted data revealed significant trends among various phospholipid classes, phosphatidylcholines, sphingomyelins, and triacylglycerols, in early-stage HGSC. Additionally, two metabolites previously linked to OC, lysophosphatidylethanolamine (18:1) and tetrahydrocortisone, were significantly elevated at the premalignant stage of HGSC development. Conversely, at this same stage, the targeted dataset showed notable increases in estrogens and glucocorticoids, while higher corticosterone levels were detected as HGSC began to develop. Overall, this study highlights the disruption of specific metabolites, phospholipid classes, and steroid hormones, in relation to HGSC tumor development under P4 treatment, suggesting their potential roles in OC development.
Advances in deciphering intratumoral versus peritumoral heterogeneity of infiltrating lymphocytes in pancreatic cancer: a spatial perspective.
Zhao K, Yang Q, Yan Y … +2 more , Zhu J, Zheng S
Transl Oncol · 2026 Aug · PMID 42224953 · Full text
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by a profoundly immunosuppressive and spatially heterogeneous tumor microenvironment. Recent research has focused on the...
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by a profoundly immunosuppressive and spatially heterogeneous tumor microenvironment. Recent research has focused on the distinct topographic distribution of tumor-infiltrating lymphocytes (TILs) across intratumoral and peritumoral compartments. This review synthesizes the latest advances, delineating the distribution, functional states, and ontogeny of region-specific TIL subsets, and dissects how spatial heterogeneity fuels disease progression and resistance to immunotherapy. We further explore the reciprocal crosstalk between immunosuppressive stroma and lymphocyte heterogeneity, highlight prevailing technical and conceptual challenges, and outline emerging technologies poised to shape the next phase of discovery. This work provides a comprehensive roadmap to accelerate translation in PDAC immuno-oncology.
Current opinions on CEA in the diagnosis and prognosis of colorectal cancer.
Han Q, Zhu Y, Xing F … +1 more , Xia Y
Transl Oncol · 2026 Aug · PMID 42214175 · Full text
Colorectal cancer (CRC), marked by high mortality and recurrence rate, poses a significant threat to public health. Differences in survival rates exist, with patients in CRC stage IV much worse than those in stage I and...
Colorectal cancer (CRC), marked by high mortality and recurrence rate, poses a significant threat to public health. Differences in survival rates exist, with patients in CRC stage IV much worse than those in stage I and stage II. Carcinoembryonic antigen (CEA) has gained widespread use as a tumor marker for CRC. The method is easy to assess, inexpensive, noninvasive, with many advantages in monitoring the prognosis. However, its effectiveness in early detection of CRC leaves much to be desired. In this review, we summarized the current applications of CEA and discussed the innovative usage of CEA as a biomarker in CRC to facilitate a much more precise predictive and prognostic strategy. What's more, we concluded the biological features of CEA, involving its structure and gene regulation, and the roles of CEA in CRC progression and metastasis.
Therapeutic vaccines targeting solid tumors: A series of clinical trial analysis over the past decade.
Qiu F, Sun Y, Lim DW
Transl Oncol · 2026 Aug · PMID 42208245 · Full text
Therapeutic cancer vaccines hold great promise, yet their clinical efficacy in solid tumors remains modest. We systematically analyzed 86 clinical trials published between 2015 and 2025 evaluating therapeutic vaccines ac...
Therapeutic cancer vaccines hold great promise, yet their clinical efficacy in solid tumors remains modest. We systematically analyzed 86 clinical trials published between 2015 and 2025 evaluating therapeutic vaccines across mRNA, DNA, peptide, dendritic cell, virus vector, and whole tumor cell platforms to understand their clinical utility and key challenges in development. Peptide-based vaccines dominated, while mRNA vaccines showed the fastest growth, often combined with immune checkpoint inhibitors. Among 1588 patients with advanced disease, the disease control rate was 53 % and the objective response rate 18 %. In adjuvant settings, 52 % of 461 patients experienced recurrence. Although 67 % exhibited ELISPOT-positive T-cell responses, no correlation with clinical efficacy was observed. Most adverse events were mild to moderate, with pyrexia, fatigue, and injection-site reactions predominating. Therapeutic vaccines thus demonstrate favorable safety and immunogenicity, but limited monotherapy efficacy, underscoring the need for combinatorial approaches and identifying personalized immunogenic neoantigens to enhance clinical benefit.
Sotorasib combined with 3-methyladenine for the treatment of KRAS G12C-mutant pancreatic cancer and its underlying mechanisms.
Li Y, Zhou M, Pan J … +9 more , Su H, Song M, Guan Z, Zhao D, Zhao X, Zhao Y, Chen P, Zhang S, Lv Y
Transl Oncol · 2026 Aug · PMID 42190605 · Full text
Pancreatic cancer is a gastrointestinal malignancy with an insidious onset and rapid progression. Due to limited therapeutic strategies, its mortality remains high. The KRAS gene is among the most frequently mutated gene...
Pancreatic cancer is a gastrointestinal malignancy with an insidious onset and rapid progression. Due to limited therapeutic strategies, its mortality remains high. The KRAS gene is among the most frequently mutated genes in solid tumors, and the development of drugs targeting KRAS mutations in pancreatic cancer is a current research focus. Sotorasib (AMG510) is the first small-molecule KRAS G12C-targeted inhibitor approved by the FDA for clinical use and has demonstrated safety and antitumor activity in tumors such as colorectal cancer and non-small cell lung cancer. At present, studies on the mechanisms of AMG510 in KRAS G12C-mutant pancreatic cancer are still at an early stage. This study aimed to investigate the effects of AMG510 on KRAS G12C-mutant pancreatic cancer cells and to preliminarily explore its mechanism of action. AMG510 inhibited the initiation and progression of KRAS G12C-mutant pancreatic cancer by inducing reactive oxygen species (ROS) accumulation, mitochondrial damage, cell cycle arrest, and apoptosis. RNA-seq revealed that AMG510 triggered cytoprotective autophagy in KRAS G12C-mutant pancreatic cancer. Treatment with the combination of AMG510 and the early autophagy inhibitor 3-methyladenine(3-MA) further suppressed proliferation and promoted apoptosis. Mouse experiments confirmed the biosafety and efficacy of AMG510 combined with 3-MA in vivo. The results of this study revealed that AMG510 exhibited favorable antitumor activity against KRAS G12C-mutant pancreatic cancer in vitro and in vivo, and the combination of AMG510 and 3-MA may represent a candidate therapeutic regimen for the clinical treatment of KRAS G12C-mutant pancreatic cancer.
Integrative multi-omics and network analysis identify potential targets of Chaihu Shugan Xiaozheng Formula in breast cancer.
Luo T, Xue M, Du Y … +3 more , Chen H, Sun Y, Sun H
Transl Oncol · 2026 Aug · PMID 42184719 · Full text
BACKGROUND: Breast cancer (BC) is linked to emotional stress and neuroendocrine-immune dysregulation. Chaihu Shugan Xiaozheng Formula (CSXF) shows clinical efficacy in BC with depressive symptoms, yet its mechanisms rema...
BACKGROUND: Breast cancer (BC) is linked to emotional stress and neuroendocrine-immune dysregulation. Chaihu Shugan Xiaozheng Formula (CSXF) shows clinical efficacy in BC with depressive symptoms, yet its mechanisms remain unclear. This study aims to investigate the therapeutic effects of CSXF in modulating neuroendocrine-immune networks and tumor-related pathways in BC. METHODS: The bioactive compounds of CSXF were screened using the TCMSP database. Target genes that intersected with differentially expressed genes associated with BC from the TCGA-BRCA dataset were analyzed. Prognostic signatures were constructed through Cox and LASSO regression models. Multi-omics profiling included immune infiltration, pathway enrichment, molecular docking, and RT-qPCR validation in BC tissue samples. RESULTS: Five core targets formed a prognostic model with high predictive accuracy. High-risk patients exhibited elevated mortality independent of age/NM stage. Oxidative phosphorylation activation and myeloid-derived suppressor cell infiltration correlated with CD14 overexpression in high-risk groups. RT-qPCR confirmed tumor-specific downregulation of CD14, PPARG, and CHRM1 in BC tissues. CONCLUSIONS: CSXF treats BC via multi-target modulation of neuroendocrine-immune and tumor pathways, providing prognostic biomarkers and mechanistic insights.
The silent pharmacist: Harnessing the gut microbiome to improve therapy in hematologic malignancies.
El-Sehrawy AAMA, Soleimani Samarkhazan H
Transl Oncol · 2026 Aug · PMID 42184718 · Full text
The gut microbiome, a complex ecosystem of microorganisms, is now recognized as a key determinant of drug efficacy and toxicity, giving rise to the field of pharmacomicrobiomics. This review decodes the profound influenc...
The gut microbiome, a complex ecosystem of microorganisms, is now recognized as a key determinant of drug efficacy and toxicity, giving rise to the field of pharmacomicrobiomics. This review decodes the profound influence of the gut microbiome on treatment outcomes for hematologic malignancies. We explore the tripartite mechanistic pathways through which gut microbes act: the direct enzymatic biotransformation of chemotherapeutic agents, the indirect immunomodulation of systemic and anti-tumor responses, and the preservation of mucosal barrier integrity to prevent devastating complications like graft-versus-host disease (GVHD). The manuscript details how the microbiome interacts with specific drug classes, from conventional chemotherapies like cyclophosphamide to cutting-edge immunotherapies like immune checkpoint inhibitors and CAR-T cells, shaping their clinical success. Furthermore, we discuss the translational potential of targeting this "silent pharmacist" through fecal microbiota transplantation, next-generation probiotics, and dietary interventions. Finally, we highlight the main translational opportunities, current limitations, and future clinical priorities for integrating microbiome science into hematology, paving the way for more personalized and improved cancer care.
Corrigendum to "Circular RNA circAHSA1 Serves as a Stable Serum Biomarker for the Diagnosis and Progression of Gastric Cancer" [Translational Oncology 63 (2026)102620].
He J, Ma S, Kuai S … +1 more , Ju S
Transl Oncol · 2026 Jul · PMID 42178712 · Full text
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Integrated histopathology-transcriptomic biomarker enhances survival prediction in HNSCC patients treated with immunotherapy.
Belete M, Thakkar N, Khatri I … +10 more , Guan M, Sun Y, Muthuswamy A, Kolder I, Si H, Soong D, Higgs BW, Brady LK, Zou J, Sridhar S
Transl Oncol · 2026 Aug · PMID 42176558 · Full text
Recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains a challenging disease with modest response to immune checkpoint inhibitors and a need for more robust predictive biomarkers. In a real-wo...
Recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains a challenging disease with modest response to immune checkpoint inhibitors and a need for more robust predictive biomarkers. In a real-world (RW) cohort of patients treated with pembrolizumab alone or in combination with chemotherapy, we evaluated transcriptomic and histopathologic features associated with therapeutic benefit. PD-L1 expression, measured by combined positive score (CPS), was not significantly associated with progression-free survival (PFS). In contrast, immune-related gene signatures, particularly those linked to T cells and tertiary lymphoid structures (TLS), were predictive of improved outcomes. TLS presence identified from Hematoxylin and Eosin-stained (H&E) whole slide images correlated with favorable survival and showed association with RNA-derived TLS signatures. TLS-associated features demonstrated treatment-specific prognostic patterns, with stronger predictive power in pembrolizumab monotherapy versus combination therapy. We developed multimodal risk prediction models integrating molecular features with imaging data which better associated with RW outcomes. Evaluation using concordance index analysis revealed that traditional pathological markers and individual molecular signatures had modest predictive capability. Digital pathology features achieved better performance than clinical or molecular features alone, but the combination of imaging and molecular features yielded the highest predictive accuracy with concordance index values of 0.86 and 0.81 in pembrolizumab and combination therapy cohorts, respectively. Kaplan-Meier analysis confirmed that our multimodal risk signature achieved significant separation between high- and low-risk groups in both treatment arms, substantially outperforming molecular features alone. These findings highlight that integrating transcriptomic and histopathological data enables precise patient stratification for immunotherapy in R/M HNSCC.
Non-invasive predictive model for incidental gallbladder carcinoma based on multimodal features: Integrating clinical data, MRI radiomics, and deep transfer learning features.
Gao Q, Liu T, Song H … +11 more , Hu Y, Ren S, Li Z, Yang H, Liu L, Chang X, Liu Y, Wang F, Zhao D, Liu X, Wang Z
Transl Oncol · 2026 Aug · PMID 42172792 · Full text
Gallbladder carcinoma, among the most prevalent malignancies of the biliary system, often presents with insidious early symptoms. Delayed diagnosis of incidental gallbladder carcinoma frequently leads to therapeutic dela...
Gallbladder carcinoma, among the most prevalent malignancies of the biliary system, often presents with insidious early symptoms. Delayed diagnosis of incidental gallbladder carcinoma frequently leads to therapeutic delays, significantly compromising patient prognosis. Clinical data,preoperative Magnetic Resonance Imaging examinations, and histopathological records from incidental gallbladder carcinoma patients were retrospectively enrolled. An integrated noninvasive predictive model was developed by combining deep learning features extracted from Magnetic Resonance Imaging radiomics with key clinical predictors. Data from 299 patients with benign gallbladder disease and 106 incidental gallbladder carcinoma cases were analyzed. Multimodal deep learning algorithms identified an optimal predictive model. Multivariate analysis revealed hemoglobin, direct bilirubin, age, distance of the cystic duct from the confluence of right and left hepatic ducts, and diameter of the common bile duct as independent predictors of incidental gallbladder carcinoma (all P<0.01). The multimodal combined feature-based prediction model (AUC=0.894[95%CI 0.829-0.960]) surpassed unimodal models (Clinic:0.862 [ 95%CI 0.787-0.936]; Rad: 0.797 [ 95%CI 0.716-0.878]; DLR: 0.844[ 95%CI 0.775-0.912]) in test cohort. Haemoglobin, direct bilirubin,age, distance of the cystic duct from the confluence of right and left hepatic ducts, and diameter of the common bile duct constitute independent predictors of incidental gallbladder carcinoma. The multimodal combined feature-based prediction model significantly outperforms single-modality models, offering a robust tool for preoperative risk stratification.
Exploring the role of 4D printing materials, techniques, and characteristics for personalized oncology.
Ashique S, Garg A, Islam A … +6 more , Taj T, Adhikary K, Ghazanfar S, Mojgani N, Hussain S, Taghizadeh-Hesary F
Transl Oncol · 2026 Aug · PMID 42166814 · Full text
Cancer is still a global concern. Cancer management is intricate in all fields, from diagnosing or defining prognosis to selecting appropriate treatment and managing its adverse effects. In recent years, three-dimensiona...
Cancer is still a global concern. Cancer management is intricate in all fields, from diagnosing or defining prognosis to selecting appropriate treatment and managing its adverse effects. In recent years, three-dimensional printing (3DP) innovations have emerged as a ground-breaking technology, offering new possibilities for cancer management. 3DP has advanced further with the addition of a fourth dimension, time, resulting in the concept of four-dimensional printing (4DP), ultimately revolutionizing the approach to cancer management. The 4DP technique has gained attention for its potential applications in cancer therapeutics. It is the next generation of the 3DP technique, which facilitates the advanced fabrication of dynamic constructs. The dynamic nature of 4D materials introduces the element of time, allowing for the observation of temporal changes in cancer behavior and response to therapeutic interventions. The use of 4DP in cancer research holds great promise for advancing our understanding of the disease and improving the translation of preclinical findings to clinical applications. However, 4DP is still in the early stages; thus, research is needed to prove its feasibility in healthcare applications. This review will illustrate the mechanisms used to induce the dynamic constructs of 4DP in cancer management. The recent potential applications of 4DP in cancer therapeutics will be further detailed, and future perspectives and conclusions will finally be proposed.
Molecular profiling and personalized medicine within EURACAN in the SPECTA Arcagen study in comparison to the France Genomic Medicine 2025 Plan in the AURAGEN platform in peritoneal mesotheliomas.
Momenkhan S, Morfouace M, Kepenekian V … +9 more , Glehen O, Villeneuve L, Oliveira J, Tejpar S, Isaac S, Fontaine J, Blay JY, Péron J, Benzerdjeb N
Transl Oncol · 2026 Jul · PMID 42150333 · Full text
Peritoneal mesothelioma (PM) is a rare aggressive cancer with limited therapeutic options upon progression. Two genomic profiling initiatives were launched to implement personalized medicine in rare cancers: the EURACAN...
Peritoneal mesothelioma (PM) is a rare aggressive cancer with limited therapeutic options upon progression. Two genomic profiling initiatives were launched to implement personalized medicine in rare cancers: the EURACAN molecular profiling and personalized medicine pathway and the France Genomic Medicine 2025 plan (AURAGEN). The aim of this study was to describe initial findings in PM and to compare these approaches in a real-world implementation setting. Herein, we present the results from a cohort of 56 patients with PM. Females represented 55.4% of patients; mean age was 55.9 years. The European (Arcagen) study profiled 26 patients and the AURAGEN platform profiled 42 patients. Genomic sequencing was performed using Foundation Medicine for the Arcagen cohort and whole-genome sequencing (WGS) for the AURAGEN cohort. Arcagen used FFPE tissue or blood depending on material availability, whereas AURAGEN relied on fresh frozen tumor tissue with paired blood (and RNA sequencing when feasible). Both cohorts displayed a predominance of alterations in BAP1, NF2, and CDKN2A/B. One patient with an ALK::STRN fusion was treated with Alectinib. AURAGEN identified a larger number of altered genes overall, while the proportion of therapeutic targets was similar between approaches. In conclusion, comprehensive molecular profiling offers potential therapeutic strategies for PM patients. Panel-based profiling and pan-genomic WGS appear complementary in real-world practice, each with distinct strengths and limitations.
A RIPK2 activity signature in prostate cancer: Modulation by RIPK2 inhibition and clinical association.
Elgehama AM, Yang Q, Pires Sanches JG … +4 more , He Z, Ruegg L, You S, Yang W
Transl Oncol · 2026 Jul · PMID 42143470 · Full text
Receptor-interacting protein kinase 2 (RIPK2) has emerged as a promising therapeutic target in multiple malignancies, including prostate cancer (PC). However, the lack of reliable biomarkers to assess RIPK2 activity limi...
Receptor-interacting protein kinase 2 (RIPK2) has emerged as a promising therapeutic target in multiple malignancies, including prostate cancer (PC). However, the lack of reliable biomarkers to assess RIPK2 activity limits patient selection and pharmacodynamic evaluation in anti-RIPK2 therapeutic strategies. To address this need, we performed RNA sequencing of three PC cell lines (22Rv1, DU145, and PC3) with CRISPR/Cas9-mediated RIPK2 knockout using two independent guide RNAs. This analysis identified 13 candidate RIPK2-regulated genes, eight of which were validated by reverse transcription quantitative PCR and incorporated into a RIPK2 activity signature. Pharmacological inhibition of RIPK2 using two structurally distinct inhibitors significantly reduced RIPK2 signature scores in five independent PC cell lines in a dose- and/or time-dependent manner. Consistently, RIPK2 inhibition progressively suppressed signature scores in vivo, supporting its utility as a pharmacodynamic readout of RIPK2 signaling output. Elevated RIPK2 signature scores were associated with metastatic disease and adverse clinical outcomes and demonstrated stronger clinical associations than RIPK2 mRNA expression alone. Mechanistic analyses identified c-Myc and KDM5A as candidate mediators of RIPK2-dependent regulation of the signature genes. Together, these findings define a RIPK2-regulated gene signature that provides a framework for patient stratification and pharmacodynamic assessment in future RIPK2-targeted clinical studies.
Multi-Omics profiling identify NNMT in tumor endothelium as a key regulator of CD8⁺ T cell exhaustion via the TGF signaling pathway.
Wang L, He H, Su K … +7 more , Gao Y, Luo Y, Tan H, Liu Z, Xu K, Li Y, Li X
Transl Oncol · 2026 Jul · PMID 42140035 · Full text
BACKGROUND: CD8⁺ T cell exhaustion is a defining feature of the immunosuppressive TME in ccRCC. METHODS: We employed a multi-omics driven pipeline to nominate Nicotinamide N-methyltransferase (NNMT) as a high-confidence...
BACKGROUND: CD8⁺ T cell exhaustion is a defining feature of the immunosuppressive TME in ccRCC. METHODS: We employed a multi-omics driven pipeline to nominate Nicotinamide N-methyltransferase (NNMT) as a high-confidence therapeutic target in ccRCC. This computational prediction was validated through bulk RNA-seq, single-cell RNA sequencing, and spatial transcriptomics to delineate NNMT-associated molecular and cellular programs. While the discovery phase highlighted endothelial-specific NNMT overexpression, we further validated the functional consequences of NNMT modulation using Caki-1 and A498 cell lines to model the downstream signaling cascades. Functional assays assessed impacts on proliferation, apoptosis, cytokine secretion (IL-6, IL-1β, TNF-α), and TGF-β pathway activity. Immune infiltration and T cell exhaustion signatures were evaluated across TCGA cohorts. RESULTS: Multi-omics profiling revealed that NNMT is specifically overexpressed in tumor-associated endothelial cells enriched for active TGF-β signaling and inflammatory cues. High NNMT expression strongly correlated with CD8⁺ T cell exhaustion, elevated apoptotic signaling, and immunosuppressive cytokine production. In functional validation, NNMT knockdown suppressed TGF-β activity, reduced pro-inflammatory cytokines, and restored CD8⁺ T cell infiltration and effector function. Mechanistically, NNMT loss shifted the BAX/Bcl-2 ratio toward apoptosis and increased cleaved caspase-3. Spatial transcriptomics confirmed that NNMT⁺ endothelial cells form an immunosuppressive niche in direct contact with exhausted T cells. We also found that I-BET-762, I-BET-151, PFI-1, and BMS-387032 can target and inhibit NNMT to reduce CD8⁺ T cell exhaustion. CONCLUSION: We establish NNMT as a central metabolic-immune hub that orchestrates TGF-β-mediated CD8⁺ T cell dysfunction and endothelial reprogramming in ccRCC.
JOSD1 stabilizes SULF1 to activate Wnt7B-FZD1 signaling in gastric cancer.
Liu L, Ma Z, Zhang Y … +4 more , Ye Z, Li H, Shi W, Jiao Z
Transl Oncol · 2026 Jul · PMID 42140034 · Full text
BACKGROUND: Aberrant activation of Wnt/β-catenin signaling is a major driver of Gastric cancer (GC) progression. However, the upstream mechanisms that sustain receptor-ligand engagement within this pathway remain insuffi...
BACKGROUND: Aberrant activation of Wnt/β-catenin signaling is a major driver of Gastric cancer (GC) progression. However, the upstream mechanisms that sustain receptor-ligand engagement within this pathway remain insufficiently characterized. METHODS: Comprehensive analyses of GC cohorts and tissue microarrays were performed to evaluate Josephin Domain Containing 1 (JOSD1) expression and its clinical significance. The impact of JOSD1 on cell proliferation, migration, invasion, apoptosis, and epithelial mesenchymal transition (EMT) was examined in vitro employing CCK-8, colony formation, Transwell, flow cytometry, Western blotting, and immunofluorescence assays. Subcutaneous xenograft models were used to assess the effects of JOSD1 on tumor growth in vivo. Mechanistic studies, including co-immunoprecipitation, ubiquitination, and rescue experiments, were employed to elucidate the molecular relationship between JOSD1, Heparan sulfate 6-O-endosulfatase 1 (SULF1), and the Wnt7B/FZD1/β-catenin signaling axis. RESULTS: JOSD1 expression was markedly elevated in GC tissues (log₂ FC > 1, FDR < 0.05) and correlated with advanced stage (P < 0.05) and poor patient prognosis (HR > 1, log-rank P < 0.05). Functionally, JOSD1 promoted GC cell proliferation, invasion, and EMT, while inhibiting apoptosis (P < 0.05). Mechanistically, JOSD1 functioned as a critical deubiquitinase that stabilized SULF1. Stabilized SULF1 directly bound the Wnt co-receptor Frizzled class receptor 1 (FZD1) and facilitated Wnt7B-FZD1 complex formation (P < 0.05), thereby activating canonical Wnt/β-catenin signaling and inducing β-catenin nuclear accumulation (P < 0.05). Ubiquitination and rescue assays confirmed that JOSD1-driven oncogenic effects were strictly dependent on SULF1 stabilization (P < 0.05). In vivo modulation of the JOSD1-SULF1 axis significantly altered tumor growth, apoptotic activity, EMT marker expression, and Wnt pathway activation (P < 0.05). CONCLUSION: JOSD1 functions as a critical deubiquitinase that stabilizes SULF1 to activate Wnt/β-catenin signaling, thereby driving GC progression. Targeting the JOSD1-SULF1-Wnt7B/FZD1/β-catenin axis may provide a promising therapeutic strategy for patients with GC.
An ac4C-CDK4 regulatory axis driven by NAT10 sustains proliferative signaling in colorectal cancer.
Qin J, Shen Y, Li S … +5 more , Hu S, Song F, Jin T, Wu J, Xu J
Transl Oncol · 2026 Jul · PMID 42127733 · Full text
BACKGROUND: N-acetyltransferase 10 (NAT10) is an RNA acetyltransferase that catalyzes N4-acetylcytidine (ac⁴C) modification and regulates mRNA stability. However, its biological function and mechanistic role in colorecta...
BACKGROUND: N-acetyltransferase 10 (NAT10) is an RNA acetyltransferase that catalyzes N4-acetylcytidine (ac⁴C) modification and regulates mRNA stability. However, its biological function and mechanistic role in colorectal cancer (CRC) remain poorly defined. METHODS: NAT10 expression was analyzed across multiple GEO cohorts and paired CRC clinical specimens. Gain- and loss-of-function experiments were performed to assess the effects of NAT10 on CRC cell proliferation, migration, colony formation, and tumor growth in vivo. Transcriptomic correlation and enrichment analyses were used to identify NAT10-associated pathways. RIP-seq mining, NAT10-RIP-qPCR, and ac⁴C-RIP-qPCR were applied to verify downstream targets. Actinomycin D chase assays were used to evaluate mRNA stability. The functional relevance of CDK4 was examined using genetic NAT10 perturbation, Remodelin-based pharmacologic treatment, and CDK4 rescue experiments. RESULTS: NAT10 was markedly up-regulated in CRC tissues compared with normal mucosa and was maintained at high levels in malignant CRC lesions. NAT10 overexpression enhanced CRC cell proliferation, migration, and colony formation, whereas NAT10 knockout suppressed these phenotypes. In vivo, NAT10-deficient cells formed significantly smaller and slower-growing xenograft tumors, with markedly reduced tumor volume and weight compared with controls. Pathway analyses indicated strong enrichment of cell-cycle programs, particularly the G1/S transition. CDK4 was identified as a NAT10-associated ac⁴C-modified target. NAT10 depletion destabilized CDK4 mRNA, reduced CDK4-associated cell-cycle protein expression, and induced G1/S accumulation, while NAT10 overexpression produced the opposite effects. Remodelin treatment, used as a pharmacologic perturbation of NAT10-associated signaling, suppressed CDK4 expression and CRC cell growth, and CDK4 overexpression partially rescued these inhibitory effects. CONCLUSIONS: This study identifies a mechanistic NAT10-ac⁴C-CDK4 regulatory axis that stabilizes CDK4 mRNA, promotes G1/S transition, and drives CRC progression. Targeting NAT10 or its downstream CDK4 pathway represents a potential therapeutic strategy for CRC.
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