Translational Oncology[JOURNAL]
Sun
200 papers
Single-cell spatial landscape of aggrephagy activity stratifies hepatocellular carcinoma neutrophils and delivers a 5-gene diagnostic panel for patient stratification.
Jiang W, Wang K, Li G … +1 more , Zhang Q
Transl Oncol · 2026 Jul · PMID 42401103 · Publisher ↗
BACKGROUND: Hepatocellular carcinoma (LIHC) features a complex tumor microenvironment (TME) where tumor-associated neutrophils (TANs) show significant plasticity. The role of aggrephagy-selective autophagy of protein agg...
BACKGROUND: Hepatocellular carcinoma (LIHC) features a complex tumor microenvironment (TME) where tumor-associated neutrophils (TANs) show significant plasticity. The role of aggrephagy-selective autophagy of protein aggregates-in shaping neutrophil heterogeneity and LIHC progression remains poorly understood. METHODS: We integrated scRNA-seq (183,671 cells), spatial transcriptomics, and bulk datasets (TCGA, GSE39791). Neutrophils (n=12,547) were re-clustered into six subsets, and aggrephagy activity was quantified via UCell scores. Analysis included pseudotime trajectories, cell-cell communication, metabolic scoring, and machine-learning-based feature selection, followed by in vitro functional validation. RESULTS: Aggrephagy activity was significantly elevated in tumor tissues compared with adjacent normal tissues (P < 0.001) and showed strong cell-type specificity, with TANs among the most enriched populations. High-aggrephagy neutrophils exhibited an undifferentiated state, preferential tumor enrichment, and a positive correlation with transcriptomic risk scores. Trajectory analysis positioned these cells at an early differentiation branch and revealed dominant neutrophil-to-stroma signaling through the CCL3-CCR1, SPP1-CD44, and ANXA1-FPR1 axes. Metabolically, high-aggrephagy neutrophils displayed enhanced inflammatory and epithelial mesenchymal-transition programs alongside suppressed oxidative phosphorylation. Integrative network analysis identified a five-gene diagnostic panel (SQSTM1, WDFY3, DOCK4, CD177, LIMK2) with robust performance across bulk cohorts (AUC 0.83-0.91). Among these, LIMK2 marked a highly interactive neutrophil subset and functionally promoted tumor cell proliferation, survival, migration, and invasion in vitro. CONCLUSION: Aggrephagy is associated with a pro-tumorigenic, metabolically reprogrammed neutrophil state in LIHC. The LIMK2-centered gene panel provides a robust framework for subset identification and nominates candidate targets for future autophagy- and neutrophil-directed studies.
Patient stratification in exercise oncology: matching exercise modalities to immune phenotypes to optimize immunotherapy response.
Zeng L, Du X, Yang Z … +5 more , Wu Y, Tang M, Liang F, Chen L, Ye X
Transl Oncol · 2026 Jul · PMID 42398463 · Publisher ↗
Despite advances in oncology, the clinical response to treatments, particularly immunotherapy, remains highly variable due to the complex tumor immune microenvironment. While regular exercise is recognized as a supportiv...
Despite advances in oncology, the clinical response to treatments, particularly immunotherapy, remains highly variable due to the complex tumor immune microenvironment. While regular exercise is recognized as a supportive intervention to improve patient outcomes, its mechanistic integration into personalized cancer care is limited by a generalized approach to physical activity. In this review, we argue that the heterogeneity of exercise benefits stems from modality-specific immune remodeling. Evidence indicates that distinct exercise types elicit specific "immune stimulation fingerprints". Steady-state aerobic exercise primarily resolves chronic inflammation and promotes immune homeostasis; resistance training preserves the muscle-immune axis, providing critical physical and immune reserves to maintain treatment tolerance; and high-intensity interval training can provoke acute mobilization of effector immune cells. Importantly, the ability of these systemic immune adaptations to enhance treatment response depends heavily on the local tumor immune niche. To bridge the gap between systemic exercise effects and clinical outcomes, we propose the "exercise-immune matching window" model. This framework highlights that improving therapeutic efficacy-and potentially optimizing responses to immunotherapy-requires patient stratification. By aligning specific exercise modalities with the individual's baseline immunophenotype (e.g., chronic inflammation, significant immunosuppression, or immunosenescence) and treatment stage, we can maximize synergistic effects. Ultimately, transitioning from generic exercise recommendations to tailored, immune-directed prescriptions offers a practical strategy to augment comprehensive cancer management.
REG4 serves as a prognostic biomarker for pancreatic cancer with long-standing diabetes mellitus by modulating chemoresistance.
Choi JI, Park HJ, Park H … +10 more , Cho Y, Shin HS, Koh YI, Lee SY, Jang SI, Cho JH, Kim HS, Hwang HK, Rim JH, Lim JB
Transl Oncol · 2026 Jul · PMID 42398462 · Publisher ↗
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) in patients with diabetes mellitus (DM) represents a clinically heterogeneous subgroup, yet biomarkers that reflect diabetes-associated tumor biology and chemotherapy r...
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) in patients with diabetes mellitus (DM) represents a clinically heterogeneous subgroup, yet biomarkers that reflect diabetes-associated tumor biology and chemotherapy response remain limited. In particular, the influence of diabetes duration on treatment resistance in PDAC is poorly understood. METHODS: We performed an integrated translational analysis combining reanalysis of public single-cell RNA sequencing (scRNA-seq) datasets, clinical serum biomarker profiling, and functional validation using pancreatic cancer cell lines and patient-derived organoids. Circulating REG4 concentrations were measured in independent PDAC cohorts and correlated with diabetes duration, overall survival, and response to FOLFIRINOX. Functional relevance was assessed under diabetes-mimicking hyperglycemic conditions. RESULTS: Single-cell transcriptomic analysis demonstrated enrichment of REG4-expressing tumor cells within the classical PDAC subtype specifically in diabetic patients. Clinically, circulating REG4 concentrations were significantly elevated in PDAC patients with long-standing diabetes, and high REG4 levels were associated with poor overall survival and resistance to FOLFIRINOX exclusively in this subgroup. In contrast, no prognostic association was observed in non-diabetic or new-onset diabetic patients. In patient-derived organoids and pancreatic cancer cell lines, chronic glucose exposure induced REG4 expression, activation of WNT/β-catenin signaling, suppression of apoptotic pathways, and increased resistance to FOLFIRINOX, recapitulating key clinical features of long-standing diabetes-associated PDAC. CONCLUSIONS: These findings suggest REG4 as a candidate diabetes duration-dependent prognostic and predictive biomarker in pancreatic cancer, warranting validation in larger prospective cohorts. By linking metabolic context to chemotherapy resistance through REG4-associated signaling, this study provides a translational framework for patient stratification and treatment optimization in diabetes-associated PDAC.
Integrated multi-omics and single-cell analysis of galectins and immune associations in triple-negative breast cancer.
Ji P, Liu H, Di GH … +2 more , Shao ZM, Gong Y
Transl Oncol · 2026 Jul · PMID 42391674 · Publisher ↗
BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies. Galectins, a family of β-galactoside-binding lectins, have emerged as important mediators of tumor-immune in...
BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype lacking effective targeted therapies. Galectins, a family of β-galactoside-binding lectins, have emerged as important mediators of tumor-immune interactions, but their cell-type-specific expression patterns and functional roles within the tumor microenvironment of TNBC remain poorly defined. METHODS: We integrated bulk transcriptomic and genomic data from FUSCC (n = 465) and TCGA (n = 161) TNBC cohorts with single-cell RNA sequencing data from 26 treatment-naïve patients. We systematically assessed galectin expression, genomic alterations, prognostic significance, associations with immune checkpoints and immune infiltration, and cell-type-specific patterns linked to immune contexts and therapeutic response. RESULTS: Galectin family members showed broad dysregulation in TNBC, with recurrent copy number alterations contributing to transcriptional heterogeneity. At the bulk level, LGALS2 was associated with favorable survival, while LGALS3 predicted poor prognosis. Several galectins, including LGALS2, LGALS9, and LGALS10, exhibited positive correlations with immune checkpoint expression and enriched immune infiltration, particularly involving CD8⁺ T cells and tumor-infiltrating lymphocytes. Single-cell analysis revealed distinct galectin expression across malignant, immune, and stromal compartments, suggesting heterogeneous transcriptomically inferred immune contexts. Galectin expression also differed by treatment response: pathological complete response (pCR) to neoadjuvant chemo-immunotherapy was associated with higher LGALS3 and lower LGALS2, LGALS8, and LGALS9, while pCR to chemotherapy was linked to higher LGALS9 and lower LGALS1. CONCLUSIONS: Our study comprehensively characterizes galectin family members in TNBC, revealing their prognostic significance and association with tumor microenvironment and treatment response, and highlighting the clinical and translational relevance of galectins as candidate biomarkers and hypothesis-generating molecules for future mechanistic studies.
DAZAP2, regulated by miR-125b, contributes to inflammation-related non-small cell lung cancer progression.
Zhang Y, Sun B, Tang Y … +12 more , Lou Y, Liu K, Qian F, Zhang L, Liu H, Qiao R, Zhang B, Xia W, Zhang W, Zhong H, Lu J, Han B
Transl Oncol · 2026 Jul · PMID 42391673 · Publisher ↗
BACKGROUND: Lung cancer remains the primary cause of cancer-related mortality globally, despite significant advancements in therapeutic strategies. Overall survival rates remain unsatisfactory. Chronic inflammation and m...
BACKGROUND: Lung cancer remains the primary cause of cancer-related mortality globally, despite significant advancements in therapeutic strategies. Overall survival rates remain unsatisfactory. Chronic inflammation and microRNAs both play pivotal roles in cancer development. METHODS: This study aimed to elucidate the roles of key microRNAs in inflammation-associated non-small cell lung cancer (NSCLC) development. RESULTS: Our findings reveal a significant reduction in miR-125b expression within NSCLC cell lines when stimulated by IL-10. Furthermore, when stimulated by IFN-γ, the expression levels of miR-125b markedly increase. Enforced expression of miR-125b markedly bolstered cell proliferation, migration, and invasion, while diminishing cell apoptosis. Conversely, inhibition of miR-125b produced opposing effects. Mechanistically, DAZAP2 was identified as a direct regulatory target of miR-125b However, because both miR-125b inhibition and DAZAP2 knockdown suppressed malignant phenotypes, DAZAP2 may represent one component of a broader miR-125b-associated regulatory network rather than the sole mediator of miR-125b function. Combined inhibition of miR-125b and DAZAP2 produced more pronounced tumor-suppressive effects both in vitro and in vivo. CONCLUSIONS: Our data suggest that miR-125b and DAZAP2 are involved in the cytokine-responsive regulatory network of inflammation-related NSCLC progression.
Single-cell and machine learning-based neural regulation signature for prognosis prediction and immunotherapy response in lung adenocarcinoma.
Zheng Y, Miao X, Wang Y … +2 more , Wei S, Zhang Q
Transl Oncol · 2026 Jul · PMID 42391672 · Publisher ↗
OBJECTIVE: Lung adenocarcinoma (LUAD) molecular heterogeneity limits traditional prognostic models. Given the emerging role of neural regulation (NR) in tumor progression, we aimed to delineate NR-associated cellular phe...
OBJECTIVE: Lung adenocarcinoma (LUAD) molecular heterogeneity limits traditional prognostic models. Given the emerging role of neural regulation (NR) in tumor progression, we aimed to delineate NR-associated cellular phenotypes via single-cell RNA sequencing (scRNA-seq) and develop a robust machine-learning-derived signature (NR.Sig) to precisely assess prognosis and guide personalized immunotherapy. METHODS: We integrated three LUAD scRNA-seq cohorts and ten transcriptomic cohorts with immunotherapy records. Single-cell analyses (clustering, cell-cell communication, pseudotime trajectory) identified NR-enriched epithelial subpopulations. Using their prognostic marker genes, we evaluated 101 combinations from 10 machine learning algorithms via leave-one-out cross-validation. The combination yielding the highest C-index formed the NR.Sig model. Its prognostic accuracy, stability, and clinical utility in characterizing the tumor immune microenvironment (TME) and forecasting immunotherapy efficacy were comprehensively validated across multiple independent cohorts. RESULTS: "CRABP2-positive epithelial cells" were identified as a stem-like, NR-enriched malignant subpopulation correlating strongly with immune exhaustion. The random survival forest (RSF)-based NR.Sig achieved optimal modeling performance. Validation confirmed that NR.Sig high-risk patients had significantly shorter overall and progression-free survival. NR.Sig outperformed conventional clinical indicators and existing prognostic models, with FAM83A identified as the core hub gene. Crucially, high-risk scores inversely correlated with immune infiltration. Conversely, the low-risk group exhibited an "immune-hot" phenotype with enhanced cancer-immunity cycle activity and elevated checkpoint expression, translating to significantly higher immunotherapy response rates in independent clinical cohorts. CONCLUSION: By integrating scRNA-seq with an optimized machine learning framework, we developed and validated NR.Sig. This robust signature holds significant clinical translational value, serving as a precise molecular tool for LUAD risk stratification, prognostic assessment, and the guidance of personalized immunotherapy strategies.
Baseline value and longitudinal kinetics of circulating nucleosomes during neo-adjuvant chemotherapy in newly diagnosed ovarian cancer: Results from a GINECO/GINEGEPS study of the randomized phase II CHIVA trial.
Corbaux P, Colomban O, Lescuyer G … +27 more , Ray-Coquard I, De Rauglaudre G, Joly F, Abdeddaim C, Combe P, Blonz C, Bataillon G, Meunier J, Alexandre J, Berton D, Kaminsky MC, Bello Roufai D, Leary A, Venat L, Dohollou N, Louvet C, Lebreton C, Abadie-Lacourtoisie S, Lotz JP, Favier L, Fabbro M, Bonichon-Lamichhane N, Kurtz JE, Follana P, Pujade-Lauraine E, Payen L, You B
Transl Oncol · 2026 Jul · PMID 42385345 · Publisher ↗
PURPOSE: Circulating nucleosomes (DNA wound around histone proteins) are emerging cancer biomarkers. We investigated their association with clinical outcomes in advanced ovarian cancer. PATIENTS AND METHODS: Circulating...
PURPOSE: Circulating nucleosomes (DNA wound around histone proteins) are emerging cancer biomarkers. We investigated their association with clinical outcomes in advanced ovarian cancer. PATIENTS AND METHODS: Circulating levels and longitudinal kinetics of two nucleosomes (H3K27Me3 and H3K36Me3, log-scale) were assessed at baseline, during neoadjuvant chemotherapy after interval cytoreductive surgery, and at progression in patients with advanced ovarian cancer patients from the randomized phase II CHIVA trial. Nucleosomes were measured with Nu.Q® immunoassays,compared to those from 201 healthy subjects, and analyzed in relation to surgical outcomes, progression-free survival, with respect to the modeled CA-25 ELIMination rate constant K (KELIM) along with established clinical covariates. RESULTS: H3K27Me3 and H3K36me3 nucleosome concentrations were available for 148/188 patients. Both nucleosomes were significantly higher in ovarian cancer patients compared with healthy controls and showed correlated baseline levels. Lower baseline H3K36Me3 was independently associated with complete interval cytoreduction surgery and progression-free survival, complementary to CA-25 KELIM. Longitudinal changes in nucleosome levels showed a decrease during neoadjuvant chemotherapy, but were not associated with radiological response, completeness of interval cytoreductive surgery or progression-free survival. CONCLUSION: Baseline H3K36Me3 and H3K27Me3 levels may represent non-invasive biomarkers in advanced ovarian cancer and warrant further evaluation for their potential clinical utility.
Fractionated high-dose vitamin c sustains higher plasma trough concentrations in advanced solid tumors: a phase I clinical study.
Yin Q, Wang Y, Wu H … +7 more , Wang Q, Xu H, Long X, Peng J, Wu J, Zhou F, Yang L
Transl Oncol · 2026 Jun · PMID 42378816 · Publisher ↗
High-dose vitamin C (HDVC) has a short half‑life of approximately 2 h, and once‑daily dosing results in sub‑therapeutic plasma concentrations for most of the dosing interval, potentially limiting its pro‑oxidant antitumo...
High-dose vitamin C (HDVC) has a short half‑life of approximately 2 h, and once‑daily dosing results in sub‑therapeutic plasma concentrations for most of the dosing interval, potentially limiting its pro‑oxidant antitumor activity. In this phase I study, 18 patients with advanced solid tumors were assigned to three cohorts (n = 6 each): Group A (0.5 g/kg once daily, total daily dose 0.5 g/kg), Group B (0.5 g/kg every 12 h, total daily dose 1.0 g/kg), and Group C (0.75 g/kg every 12 h, total daily dose 1.5 g/kg). Plasma trough concentrations were measured daily for 7 days. Compared to Group A, Group B exhibited significantly higher trough concentrations throughout the study (P < 0.05), demonstrating superior maintenance of therapeutic levels. Further dose escalation to 0.75 g/kg twice daily (Group C) provided no additional trough concentration benefit versus Group B (P > 0.05), consistent with the plateau in peak concentrations at single doses above approximately 70 g/m² (∼1.0 g/kg). All regimens were well tolerated, with only one mild nausea (5.6%) and no serious adverse events. Fractionated dosing (0.5 g/kg every 12 h) significantly improves trough concentration maintenance with good tolerability. This optimized regimen (total daily dose 1.0 g/kg) provides a rational pharmacokinetic basis for future phase II trials designed to evaluate whether sustained pro‑oxidant levels translate into enhanced clinical efficacy.
Mechanisms and advances of drug resistance in colorectal cancer: A systematic overview of multi-layered regulatory networks.
Qiu S, Li S, Chen Y … +3 more , Ma X, Fu H, Zhao B
Transl Oncol · 2026 Jun · PMID 42378815 · Publisher ↗
Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. Although substantial advances in chemotherapy, molecular targeted therapy, and immunotherapy have improved clinical out...
Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. Although substantial advances in chemotherapy, molecular targeted therapy, and immunotherapy have improved clinical outcomes in select patient populations, therapeutic resistance remains the major obstacle to durable disease control. Accumulating evidence suggests that drug resistance in CRC does not result from isolated molecular events, but rather reflects a dynamic and adaptive process driven by coordinated tumor intrinsic programs, as well as continuous interactions between tumor cells and their surrounding microenvironment. In this Review, we present a systematic overview of the clinical manifestations and biological foundations of resistance to cytotoxic chemotherapy, targeted therapy, and immune checkpoint blockade in CRC. We summarize tumor intrinsic resistance mechanisms, including oncogenic signaling reprogramming, DNA damage response modulation, metabolic and redox adaptation, ubiquitin-regulated proteostasis, epigenetic and RNA-mediated regulation, evasion of programmed cell death, and the emergence of cancer stem cell and drug-tolerant persister states. In parallel, we examine the contribution of the tumor microenvironment, including cancer-associated fibroblasts, immunosuppressive immune networks, extracellular vesicle-mediated communication, and the gut microbiota, in establishing protective niches that promote resistance and limit therapeutic efficacy. We further discuss how emerging approaches such as single-cell and spatial multi-omics profiling, liquid biopsy, and longitudinal molecular monitoring have reshaped the understanding of drug resistance as a continuous evolutionary process under therapeutic selection pressure. Finally, we highlight therapeutic strategies inspired by systems biology and evolutionary principles, with an emphasis on rational combination and sequencing regimens, targeting adaptive vulnerabilities, and remodeling the tumor ecosystem to enable more durable and precise control of CRC.
Establishment of a clear cell renal cell carcinoma organoid cohort integrated into the UroCCR clinical database: A feasibility study.
Lefranc R, Waeckel T, Riffet M … +9 more , Florent R, Desmartin G, Lecouflet L, Divoux J, Poulain L, Tillou X, Weiswald LB, Levallet G, Bazille C
Transl Oncol · 2026 Jun · PMID 42372405 · Publisher ↗
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the sixth most common cancer in France. While early-stage survival rates are high in early stages, they decrease significantly in metastatic stages, due to tumor het...
BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the sixth most common cancer in France. While early-stage survival rates are high in early stages, they decrease significantly in metastatic stages, due to tumor heterogeneity and treatment resistance. The development of reliable preclinical models is essential to improve targeted therapies. This study aimed to evaluate the feasibility of establishing patient-derived ccRCC organoids linked to the UroCCR clinical database. METHODOLOGY: Tumor samples from total or partial nephrectomies performed at Caen University Hospital between November 2023 and March 2024 were processed for organoid culture. Seven culture conditions were tested, including different extracellular matrices (Matrigel, collagen I) and growth factor-enriched media. RESULTS: Organoids were established in 12 of 18 cases (66.7%). Among these, five cultures were successfully expanded and characterized histologically (42%). Organoids were maintained in culture for a median of 52 days and underwent a mean of two passages. Histological analyses showed that organoids retained several morphological features consistent with the original tumors, although variability in CA-IX and CK7 expression was observed. SIGNIFICANCE: This feasibility study demonstrates that ccRCC organoid generation from surgical specimens is achievable but remains limited by variable establishment rates and culture duration. Further optimization and integration of microenvironmental components will be necessary to enhance the translational relevance of this model.
The YAP-TEAD4 inhibitor M511-0965 suppresses triple-negative breast cancer progression by downregulating TGFB2.
Cheng M, Li X, Song N … +10 more , Yang X, Ma X, Zhang H, Lei Y, Jia Y, Ba L, Zhang R, Bai L, Xu W, Qiao G
Transl Oncol · 2026 Jun · PMID 42365824 · Full text
Triple-negative breast cancer (TNBC) lacks standard targeted therapies, and chemotherapy is associated with significant side effects and economic burden, highlighting the urgent need to develop novel low-toxicity and low...
Triple-negative breast cancer (TNBC) lacks standard targeted therapies, and chemotherapy is associated with significant side effects and economic burden, highlighting the urgent need to develop novel low-toxicity and low-cost strategies. The Hippo pathway serves as a critical regulator of organ development. Its activation phosphorylates Yes-associated protein (YAP) and transcriptional coactivator TAZ, promoting their cytoplasmic degradation and inhibiting their binding to the nuclear transcription factor TEAD, thereby suppressing downstream gene expression. As the terminal effector of this pathway, TEAD plays an important role in various tumors. In this study, bioinformatics and molecular biology experiments revealed that TEAD4 is highly expressed in TNBC, and its expression level influences the biological functions of TNBC. Thus, TEAD4 represents an important therapeutic target for tumors, underscoring the need to identify safe and low-toxicity TEAD4 small-molecule inhibitors. Structure-based virtual screening has become a key step in drug discovery. Focusing on the crystal structure of the YAP/TEAD4 complex, we employed molecular docking technology for screening and identified a novel small-molecule inhibitor. Molecular biology and cellular functional assays confirmed that this inhibitor acts by targeting the YAP/TEAD4 interaction, thereby exerting antitumor effects. This preclinical study provides new insights and experimental evidence for targeted therapy in TNBC.
Pan-cancer analysis identifies immunoproteasome as the predominant survival-associated component of antigen processing machinery.
Lai JI, Liu CY, Tsai YF … +3 more , Huang CC, Tseng LM, Chao TC
Transl Oncol · 2026 Jun · PMID 42364494 · Full text
Neoantigens are critical targets for cancer immunotherapy, yet the relationship between experimentally validated neoantigen burden and antigen processing machinery (APM) expression in determining clinical outcomes remain...
Neoantigens are critical targets for cancer immunotherapy, yet the relationship between experimentally validated neoantigen burden and antigen processing machinery (APM) expression in determining clinical outcomes remains unclear. We mapped CEDAR-annotated neoantigens (CENs) onto mutation data from 43,980 patients across 14 cancer types using cBioPortal. APM gene expression was correlated with survival outcomes across 13 cohorts. Machine learning approaches (elastic net stability selection, random survival forest, univariable Cox regression) identified prognostically important APM genes across 11 cohorts. Findings were validated in the IMvigor210 immunotherapy trial (n=348 metastatic urothelial carcinoma patients) and single-cell RNA-sequencing data (GSE161529; n=29 breast cancers). Overall, 40.4% of patients harbored at least one CEN, with high prevalence in pancreatic (>75%) and skin cancers (>70%). CENs predominantly arose from driver oncogenes including PIK3CA, KRAS, BRAF, TP53, and EGFR. High APM expression was associated with improved survival, particularly in CEN-positive tumors. Machine learning identified immunoproteasome components (PSME1, PSMB8, PSMB9, PSMB10) as the dominant prognostic contributors within the 12-gene APM signature. A simplified 4-gene immunoproteasome score performed equivalently to the full APM score in leave-one-cohort-out cross-validation (median C-index 0.545 vs 0.545; p=0.31). In IMvigor210, immunoproteasome-high patients achieved a 3.2-fold higher response rate to atezolizumab (19.8% vs 6.2%; p=0.010). Single-cell analysis confirmed that tumor-intrinsic immunoproteasome expression correlated with increased CD8+ T cell infiltration (p=0.0014) and total immune fraction (p=0.0002). The 4-gene immunoproteasome signature demonstrates robust prognostic and predictive value across bulk sequencing, clinical trial, and single-cell platforms, warranting prospective validation as an immunotherapy biomarker.
USP48 functions as a suppressor of colorectal cancer via SELENBP1 stabilization.
Lin H, Huang Y
Transl Oncol · 2026 Jun · PMID 42364493 · Full text
AIM: Colorectal cancer (CRC) is a leading cause of cancer-related death. SELENBP1 is a tumor suppressor in CRC. However, the mechanism regulating the stability of the SELENBP1 protein remains elusive. METHODS: Here, we e...
AIM: Colorectal cancer (CRC) is a leading cause of cancer-related death. SELENBP1 is a tumor suppressor in CRC. However, the mechanism regulating the stability of the SELENBP1 protein remains elusive. METHODS: Here, we explored multiple ubiquitin-specific proteases (USPs) that may control SELENBP1 stability. In vitro, USP48 was overexpressed in CRC cell lines to observe its effect on malignant behaviors of cells. The interaction between USP48 and SELENBP1 was investigated using immunoprecipitation. RESULTS: Our data showed that USP48 exhibits a robust effect in stabilizing SELENBP1. Results of bioinformatics analysis showed that although USP48 expression was variable across datasets, its prognostic signal was consistent, and it was positively correlated with the prognosis of CRC patients. USP48 expression is also decreased in multiple CRC cells, and overexpression of USP48 impaired the malignant behaviors and stemness of HCT-116 and LOVO CRC cells. At the molecular level, USP48 interacts with SELENBP1 in CRC cells. USP48 overexpression substantially decreased the ubiquitination level of SELENBP1 and enhanced its stability. Depletion of SELENBP1 in USP48-overexpressing CRC cells improved their malignant behaviors and stemness, suggesting that SELENBP1 is a key factor in mediating the tumor suppressor function of USP48 in CRC. CONCLUSION: Together, these observations deepen our understanding of the post-translational regulation of SELENBP1 and underscore the diagnostic and therapeutic potential of the USP48-SELENBP1 axis in CRC.
S100A10 promotes tumorigenesis and metastasis in lung adenocarcinoma by regulating JUND/TNC axis-mediated EMT.
Zheng Z, Peng A, Xi Z … +6 more , Ou H, Liu J, Ye A, Shao J, Li F, Liu Y
Transl Oncol · 2026 Jun · PMID 42361687 · Full text
BACKGROUND: Recurrence and metastasis significantly impact the prognosis of lung adenocarcinoma (LUAD), yet effective therapies targeting these processes remain limited, especially in advanced stages. This study investig...
BACKGROUND: Recurrence and metastasis significantly impact the prognosis of lung adenocarcinoma (LUAD), yet effective therapies targeting these processes remain limited, especially in advanced stages. This study investigates the role of S100A10 as an oncogenic driver in LUAD progression via epithelial-mesenchymal transition (EMT). METHODS: S100A10 expression was analyzed in public datasets and correlated with patient survival. Functional studies involved S100A10 knockdown or overexpression in LUAD cell lines, assessing viability (CCK-8), migration, invasion (Transwell, wound healing), mRNA (qPCR), and protein (Western blot). Tumorigenicity was evaluated using in vivo models. A small-molecule inhibitor, [D-Leu-4]-OB3, was identified through virtual screening and tested for its effect on S100A10 and LUAD. RESULTS: High S100A10 expression correlated with poor outcomes in LUAD. Knockdown of S100A10 suppressed cell viability, migration, invasion, and EMT both in vitro and in vivo, while overexpression enhanced these malignant traits. Mechanistically, S100A10 activated JUND and Tenascin-C (TNC), promoting EMT. Re-expression of TNC rescued the anti-metastatic effects of S100A10 inhibition. [D-Leu-4]-OB3 specifically targeted S100A10, inhibiting LUAD growth and metastasis. CONCLUSION: S100A10 promotes LUAD progression and metastasis through JUND/TNC-mediated EMT. [D-Leu-4]-OB3 represents a promising targeted therapy for LUAD by inhibiting S100A10.
Can manual gemcitabine instillation or tumor microenvironment-based selection enhance the efficacy of TAR-200 in bladder cancer?
Chen L, Liang C
Transl Oncol · 2026 Jun · PMID 42349319 · Full text
TAR-200, a novel intravesical drug delivery system, has demonstrated remarkable efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer, achieving a complete response rate of 82.4% in the phase IIb...
TAR-200, a novel intravesical drug delivery system, has demonstrated remarkable efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer, achieving a complete response rate of 82.4% in the phase IIb SunRISe-1 study. In this letter, we propose two strategies to further optimize treatment outcomes. First, we suggest that a single manual gemcitabine instillation given concurrently with TAR-200 placement-without adding an extra procedure - could combine the high peak concentration of manual instillation with the sustained release profile of TAR-200, potentially enhancing antitumor activity. Second, we discuss the immunological mechanisms underlying BCG failure, particularly the development of an immunosuppressive tumor microenvironment characterized by upregulation of PD-L1 on tumor and immune cells. We hypothesize that assessing baseline or BCG-induced immunosuppressive status may help identify patients who would derive greater benefit from the addition of the PD-1 inhibitor cetrelimab to TAR-200. These considerations warrant further investigation to maximize therapeutic efficacy in this challenging patient population.
Establishment, biobanking, and multi-omics characterization of 41 patient-derived colorectal cancer organoids: MYC/PRC classification.
Lee YJ, Park JH, Nam HJ … +5 more , Kim SC, Kim MJ, Jeong SY, Park JW, Ku JL
Transl Oncol · 2026 Jun · PMID 42349318 · Full text
PURPOSE: Colorectal cancer (CRC) exhibits marked genetic, transcriptomic, and phenotypic heterogeneity, limiting the robustness of existing molecular classification systems. We aimed to apply and validate an SMI-based MY...
PURPOSE: Colorectal cancer (CRC) exhibits marked genetic, transcriptomic, and phenotypic heterogeneity, limiting the robustness of existing molecular classification systems. We aimed to apply and validate an SMI-based MYC/PRC classification framework in CRC patient-derived organoids and to characterize its molecular, pharmacologic, and clinical relevance across independent cohorts. METHODS: We established 41 CRC PDOs from 28 patients and performed whole-exome sequencing, RNA sequencing, and high-throughput drug screening. SMI scores (-1 to 1) were used to classify PDOs as MYC-type (stem-like) or PRC-type (differentiated). A concordantly classified subset of 25 PDOs underwent integrative multi-omics analyses. Findings were validated in an expanded cohort of 181 CRC PDOs and in TCGA-COAD. We compared pathway activities, mutational profiles, and drug responses, and performed archetypal modeling (K = 2) to position samples along a MYC-PRC transcriptional continuum. RESULTS: MYC-type PDOs exhibited enrichment of cell-cycle and proliferation-related programs, whereas PRC-type PDOs showed differentiation-associated transcriptional programs, including coagulation and NF-κB signaling. Drug screening showed greater sensitivity of MYC-type PDOs to MEK/EGFR-targeted agents, whereas PRC-type PDOs displayed more heterogeneous responses. Archetypal modeling preserved the α(PRC)-α(MYC) trade-off and sample ordering across feature sets and larger cohorts. Validation in the expanded PDO dataset and TCGA-COAD reproduced subtype-specific transcriptional patterns and supported their clinical relevance. CONCLUSIONS: SMI-based MYC/PRC classification captures biologically coherent tumor states with distinct molecular features and therapeutic sensitivities. This transcriptome-based framework complements existing classification systems and may support subtype-informed therapeutic prioritization in CRC.
The ESR1-MYH14 axis functions as a critical driver of cervical cancer progression and metastasis.
Yi H, Li S, Han Y … +4 more , Li Q, Wang X, Xiong L, Lan Q
Transl Oncol · 2026 Jun · PMID 42349317 · Full text
BACKGROUND: Cervical cancer remains a major cause of cancer-related mortality in women, yet its molecular mechanisms of progression and metastasis are not fully defined. This study explores the oncogenic role of the ESR1...
BACKGROUND: Cervical cancer remains a major cause of cancer-related mortality in women, yet its molecular mechanisms of progression and metastasis are not fully defined. This study explores the oncogenic role of the ESR1 (estrogen receptor α)-MYH14 (myosin heavy chain 14) signaling axis in cervical cancer. METHODS: Quantitative real-time PCR and Western blotting were used to assess RNA and protein levels. The transcriptional regulation of MYH14 by ESR1 was verified through chromatin immunoprecipitation quantitative PCR and dual-luciferase assays. Cellular proliferation, migration, and invasion were evaluated using CCK-8, colony formation, wound healing, and transwell assays. Xenograft and tail vein metastasis models were applied to examine the effects of MYH14 silencing and ESR1 inhibition by AZD9833. RESULTS: MYH14 was markedly upregulated in cervical cancer tissues and correlated with poor prognosis. MYH14 knockdown suppressed proliferation and metastasis both in vitro and in vivo. ESR1 functioned as a transcriptional activator of MYH14, enhancing c-Myc and MMP9 expression, whereas MYH14 silencing or AZD9833 treatment reversed these oncogenic effects and reduced ESR1, MYH14, c-Myc, and MMP9 levels. CONCLUSION: The ESR1-MYH14 signaling axis drives cervical cancer growth and metastasis. Targeting this pathway may represent a promising therapeutic strategy for cervical cancer management.
PD-1/PD-L1 immune checkpoint inhibitors in Hodgkin lymphoma: A meta- and network meta-analysis.
Zhu T, Liu Z, Sun H … +3 more , Lin T, Lu Z, Yang X
Transl Oncol · 2026 Jun · PMID 42349316 · Full text
BACKGROUND: Hodgkin lymphoma (HL) is a relatively rare lymphoid malignancy that significantly affects the health of adolescents, young adults and the elderly. Even though conventional chemotherapy offers high cure rates,...
BACKGROUND: Hodgkin lymphoma (HL) is a relatively rare lymphoid malignancy that significantly affects the health of adolescents, young adults and the elderly. Even though conventional chemotherapy offers high cure rates, the relapsed/refractory HL remains challenging. METHODS: Pooled single-arm and network meta-analyses were used. Literature search was conducted in PubMed, Embase, Web of Science, the Cochrane Library and Clinical Trials, et al., from the date of establishment dates to August 31, 2025. Studies were screened based on inclusion and exclusion criteria. The primary outcome analyzed was complete response rate (CRR), partial response rate (PRR), and objective response rate (ORR). RESULTS: 11 single-arm trials and five controlled trials, involving 1602 participants and seven ICI-based treatment strategies were included. The meta-analysis revealed an overall CRR of 0.35, a PRR of 0.37, and an ORR of 0.75 across all therapy methods. Of these, one ICI drug in combination with conventional therapy demonstrated the highest CRR and ORR, while camrelizumab achieved the highest PRR. The treatment strategies with the highest CRR in network meta-analysis was the combination of two ICI drugs. The strategies with the highest PRR were camrelizumab, a single ICI drug, while the strategies with the highest ORR was a single ICI drug combined with conventional therapy. CONCLUSION: This study suggests that camrelizumab is associated with an improved PRR for HL, whereas, combination strategy of two ICI drugs, and that one of pembrolizumab and camrelizumab combined with conventional chemoradiotherapy are more effective for elevating the CRR and ORR respectively.
Comprehensive analysis of antibody-drug conjugate (ADC) targets in adenoid cystic carcinoma: examining antigen expression in relation to clinicopathological features, prognosis, and initial therapeutic outcomes.
Wang Y, Dou S, Jiang W … +5 more , Zhu L, Liu S, Gu T, Zhu G, Li J
Transl Oncol · 2026 Jun · PMID 42341371 · Full text
Effective systemic therapy for refractory or recurrent/metastatic adenoid cystic carcinoma (ACC) remains an unmet clinical need. Although antibody-drug conjugates (ADCs) have revolutionized treatment for other solid tumo...
Effective systemic therapy for refractory or recurrent/metastatic adenoid cystic carcinoma (ACC) remains an unmet clinical need. Although antibody-drug conjugates (ADCs) have revolutionized treatment for other solid tumors, their application in ACC is limited by an inadequate understanding of targetable antigen expression. We performed immunohistochemical analysis of five ADC targets (EGFR, TROP2, B7-H4, Nectin-4, and AXL) across 265 ACC cases (193 non-solid subtype and 72 solid subtype) and examined their expression in relation to clinicopathological features, histological subtypes, and prognosis. Additionally, we conducted preliminary biomarker-guided ADC therapy in two selected patients. EGFR and TROP2 were frequently expressed at moderate-to-high levels (81% of cases for EGFR and 77% for TROP2), mainly in non-solid ACC, with high expression rates of 72% and 55%, respectively. Conversely, B7-H4 and Nectin-4 showed moderate-to-high expression in 59% and 55% of the overall cohort, but were notably enriched in the aggressive solid subtype, with high expression observed in 66% and 75% of cases, respectively. AXL expression was either negative or low. High B7-H4 and Nectin-4 expression levels were independently associated with reduced overall survival (p < 0.05), whereas EGFR and TROP2 expression showed no significant prognostic value. Importantly, early clinical studies demonstrated that the EGFR-targeted ADC MRG003 and the TROP2-targeted ADC Sac-TMT showed notable efficacy in patients with refractory ACC and high expression of these targets. This pioneering study introduces a biomarker-based stratification system, categorizing ACC patients by histological subtype and target expression profiles, EGFR/TROP2 for non-solid ACC and B7-H4/Nectin-4 for solid ACC, to inform ADC therapy decisions.
Clinical translation of an immunomodulatory cell therapy that is designed to convert "cold" tumors to "hot": A phase 2B trial in 3L MSS/pMMR metastatic colorectal cancer.
Hirschfeld A, Al Hallak MN, Cusnir M … +5 more , Yang X, Piyapan P, Lausoontornsiri W, Shane R, Har-Noy M
Transl Oncol · 2026 Jun · PMID 42335577 · Full text
BACKGROUND: A translational immunotherapy framework was designed to initiate sequential spatial and temporal immunomodulatory cascades using living, allogeneic, activated memory Th1 cells (AlloStim®), hypothesized to pro...
BACKGROUND: A translational immunotherapy framework was designed to initiate sequential spatial and temporal immunomodulatory cascades using living, allogeneic, activated memory Th1 cells (AlloStim®), hypothesized to promote an immunomodulatory cascade in immunologically "cold" tumors. Microsatellite stable/proficient mismatch repair (MSS/pMMR) metastatic colorectal cancer (CRC) represents an immunotherapy-refractory "cold" tumor archetype with historically low response rates. METHODS: To evaluate this framework, a Phase 2B, single-arm, multi-center proof-of-concept trial was conducted in third-line MSS/pMMR metastatic CRC patients, utilizing overall survival (OS) as the primary endpoint. AlloStim® was administered via a sequential schedule of weekly intradermal priming and subsequent intravenous infusions over three 5-week cycles, followed by optional monthly intravenous boosters. RESULTS: Twenty-nine patients were enrolled (18 death events, 11 censored cases [37.9%]). The median OS was 16.4 months (492 days; 95% CI: 8.6-20.8 months). To account for non-proportional hazards, Restricted Mean Survival Time (RMST) evaluated at a 32-month temporal horizon demonstrated an average cohort life expectancy of 16.1 months (482 days; 95% CI: 12.3-19.8 months). Concurrently, 89% of evaluable patients met RECIST 1.1 criteria for progressive disease at Day 119, highlighting a profound survival-radiological discordance. The protocol was well tolerated; only 4% of total adverse events were ≥ Grade 3. CONCLUSION: This study provides indirect clinical observations supporting the hypothesis that an active immunomodulatory framework may elicit an encouraging survival signal and extended life expectancy in refractory metastatic MSS/pMMR CRC, despite conventional radiological progression. These findings justify evaluation in a prospective, randomized controlled trial powered to validate this translational strategy.
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