J Transl Med [JOURNAL]
Sun
200 papers
Deciphering elevated risk of life-threatening hemorrhage and early death in acute myeloid leukemia with APL-like phenotype: independent role of endothelial injury and implications of EASIX-based risk stratification in a multicenter study.
Shu M, Li X, Wang Y … +3 more , Wu D, Ding W, Chen S
J Transl Med · 2026 Jun · PMID 42321829 · Full text
BACKGROUND: Early hemorrhagic mortality remains the major cause of elevated early death (ED) incidence in acute promyelocytic leukemia (APL)-like subgroup of acute myeloid leukemia (AML). The underlying mechanisms remain...
BACKGROUND: Early hemorrhagic mortality remains the major cause of elevated early death (ED) incidence in acute promyelocytic leukemia (APL)-like subgroup of acute myeloid leukemia (AML). The underlying mechanisms remain unknown and risk-adapted management strategies are not well established. We aimed to investigate the significance of endothelial injury in major bleeding event (MBE) and ED of APL-like AML (APLL) using endothelial activation and stress index (EASIX), and to develop an EASIX-based risk stratification with translational implications on APLL in venetoclax (VEN) era. METHODS: This multicenter study investigated newly diagnosed AML patients from three Chinese institutions between January 2017 and September 2025. Propensity score matching (PSM) and prospective thrombomodulin (TM) measurements were applied to validate EASIX utility in APLL. The APLL cohort was divided into development and validation cohorts based on diagnostic institutions to establish an MBE risk stratification using logistic regression. RESULTS: Of 344 APLL, 212 APL, and 1596 'Other AML' in the analysis, log2-EASIX of APLL was comparable to APL but significantly higher than 'Other AML' (3.777 vs. 2.692, P < 0.001), which was sustained after PSM (4.022 vs. 2.904, P < 0.001). Significant correlation was further validated between log2-EASIX and TM (r = 0.80, P < 0.001). Within APLL, high log2-EASIX (OR: 5.611, 95% CI: 2.212-14.233, P < 0.001), overt DIC at diagnosis (OR: 2.929, 95% CI: 1.127-7.616, P = 0.027) and CD56 + blasts (OR: 3.697, 95% CI: 1.691-8.082, P = 0.001) emerged as independent MBE risk factors, setting foundation for a novel risk stratification. High-risk APLL exhibited significantly higher cumulative ED incidence in both development and validation cohorts, particularly when treated with standard VEN combining hypomethylating agent (HMA) regimen (P < 0.05 in both cohorts). However, modified VEN-HMA regimen with reduced VEN initiation dose specifically improved early outcomes of high-risk APLL (P = 0.036) in an independent, real-world implementation cohort. CONCLUSIONS: APLL is characterized by significant endothelial damage, which is quantifiable by EASIX to independently contribute to the elevated MBE risk. The EASIX-based stratification can be utilized to rapidly identify high-risk APLL, who may benefit from an optimized VEN-HMA induction strategy to reduce ED risk.
ENO1 interacts with PKM to promote HBV-related hepatocellular carcinoma progression and HBV replication.
Hu YC, Liu HJ, Gu MY … +3 more , Ma ZM, Ma LN, Ding XC
J Transl Med · 2026 Jun · PMID 42321826 · Full text
BACKGROUND: The progression of hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) is driven by complex interactions between metabolic reprogramming and viral replication. Glycolytic enzymes, including α-enola...
BACKGROUND: The progression of hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) is driven by complex interactions between metabolic reprogramming and viral replication. Glycolytic enzymes, including α-enolase (ENO1) and pyruvate kinase M (PKM), play key roles in tumor progression, but their specific contribution to HBV-associated HCC remains inadequately defined. This study investigates the molecular mechanisms by which ENO1 and PKM promote HCC progression and HBV replication. METHODS: The expression levels of ENO1 and PKM in HBV-infected HCC cells were evaluated, and their interaction was explored using co-immunoprecipitation (Co-IP), quantitative reverse transcription polymerase chain reaction (qRT-PCR), and Western blot analysis. Additionally, an HCC mouse model was employed to assess the impact of this interaction on HCC progression and HBV replication. RESULTS: Both ENO1 and PKM were significantly upregulated in HBV-associated HCC cells and mouse models. Co-IP assays revealed a direct interaction between ENO1 and PKM. Functionally, ENO1 enhanced HCC cell proliferation, migration, invasion and in vivo tumor growth. Furthermore, elevated levels of ENO1 and PKM significantly increased HBV replication, thus exacerbating HCC progression. CONCLUSIONS: This study indicated a novel mechanism in which ENO1 interacts with PKM to accelerate both HBV-related HCC progression and viral replication. These findings suggest that targeting the ENO1-PKM axis may provide a promising metabolic therapeutic approach for HBV-associated HCC.
Glycolytic reprogramming in cancer: tumour cell metabolism, immune modulation, and therapeutic opportunities.
Wang L, Liu F, Wei Y … +3 more , Jia Q, Zhu B, Chu Q
J Transl Med · 2026 Jun · PMID 42321806 · Full text
BACKGROUND: Aberrant metabolism is a hallmark of tumours. Cancer cells develop metabolic patterns distinct from those of normal cells, characterized by the conversion of glucose into lactate under both aerobic and hypoxi...
BACKGROUND: Aberrant metabolism is a hallmark of tumours. Cancer cells develop metabolic patterns distinct from those of normal cells, characterized by the conversion of glucose into lactate under both aerobic and hypoxic conditions. The intermediates and end products generated in this process modulate the function and survival of immune cells within the tumour microenvironment (TME). METHODS: In this review, we summarize recent advances in the interplay between glycolysis and the immune microenvironment, potential therapeutic targets within the glycolytic pathway, and the clinical translation of glycolysis-related molecules. MAIN BODY: Through in-depth research into the glycolytic process, it has been found that the aberrant glycolytic metabolism of tumor cells not only supports their own proliferation but also reshapes the tumor microenvironment. This, in turn, forces immune cells to alter their metabolic profiles, ultimately resulting in an imbalanced anti-tumor immune response. To date, multiple small-molecule inhibitors targeting key molecules and nodes in the glycolytic pathway have been developed, some of which demonstrate promising anti-tumor efficacy in preclinical models. CONCLUSION: The review emphasizes the significance of glycolysis in shaping the immune response within the TME and underscores the therapeutic potential of targeting glycolytic pathways, with several inhibitors showing promise for future clinical translation.
A novel Tie2xVEGF bispecific antibody fusion demonstrates enhanced therapeutic efficacy through direct Tie2 activation and VEGF neutralization.
Kwon MG, Kim SJ, Lee K … +8 more , Song JH, Lee J, Kim I, Min JK, Kwon YG, Lee DG, Lee J, Lee NK
J Transl Med · 2026 Jun · PMID 42321788 · Full text
BACKGROUND: Activation of endothelial Tie2 signaling has emerged as a potential therapeutic strategy for ameliorating vascular abnormalities and hyperpermeability in ocular diseases. Early therapeutic strategies have foc...
BACKGROUND: Activation of endothelial Tie2 signaling has emerged as a potential therapeutic strategy for ameliorating vascular abnormalities and hyperpermeability in ocular diseases. Early therapeutic strategies have focused on inhibiting angiopoietin-2 (Ang2), an antagonistic ligand of Tie2, thereby indirectly promoting Tie2 activation. However, accumulating evidence indicates that indirect Tie2 activation via Ang2 blockade is insufficient for enhanced therapeutic efficacy, underscoring the need for Tie2 agonists. In addition, since it is still necessary to inhibit neovascularization induced by vascular endothelial growth factor (VEGF), appropriate therapeutic efficacy could be achieved by direct Tie2 agonism and VEGF neutralization. METHODS: An affinity-matured Tie2-activating antibody, MT-101, was identified by phage display panning using a complementarity-determining region-targeted mutagenesis library. Tie2xVEGF bispecific antibodies were generated with MT-101 fused to five different anti-VEGF modules, and their functionality in Tie2 and VEGF signaling was compared using endothelial cells. The therapeutic efficacy of the bispecific antibody fusion MT-103, comprising MT-101 and VEGFR domains, was evaluated in mouse oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularization (LI-CNV) models compared with anti-VEGF agent Aflibercept or Ang2xVEGF bispecific antibody. RESULTS: MT-101 activated the Tie2 signaling pathway, including AKT-eNOS and ERK cascades, and exhibited efficacy comparable to that of Aflibercept in OIR and LI-CNV models. By directly comparing five different Tie2xVEGF bispecifics, we selected the most potent construct, MT-103, generated by fusing VEGFR1/2 domains to MT-101. MT-103 demonstrated approximately four- and five-fold greater potency than the Ang2xVEGF bispecific antibody in inhibiting VEGF signaling and reducing permeability, respectively, in retinal endothelial cells. MT-103 further demonstrated improved efficacy, reducing neovascularization by 14% compared with Aflibercept in the LI-CNV model and suppressing vascular leakage by 20% compared with Ang2xVEGF bispecific antibody in the OIR model. Moreover, MT-103 elicited robust Tie2 activation and vessel stabilization by enhancing pericyte coverage relative to Ang2xVEGF bispecific antibody. CONCLUSIONS: These findings demonstrate that a therapeutic strategy combining direct Tie2 activation and VEGF blockade may provide improved therapeutic potential compared to neutralizing VEGF alone or Ang2 and VEGF, representing a promising therapeutic strategy that warrants further validation for the treatment of various ocular diseases.
Pancreatic organoids and organoid-on-a-chip platforms: from disease modeling to precision therapy.
Lin M, Ma W, Ma T … +7 more , He Y, Shi H, Ge N, Guo J, Xie Y, Sun S, Yang F
J Transl Med · 2026 Jun · PMID 42321786 · Full text
BACKGROUND: Pancreatic diseases, including diabetes, pancreatic ductal adenocarcinoma, pancreatitis, and cystic fibrosis, impose a substantial clinical burden and are challenging to model using conventional experimental...
BACKGROUND: Pancreatic diseases, including diabetes, pancreatic ductal adenocarcinoma, pancreatitis, and cystic fibrosis, impose a substantial clinical burden and are challenging to model using conventional experimental systems. Pancreatic organoids provide physiologically relevant three-dimensional models that recapitulate the key structural and functional features of the human pancreas. This review summarizes recent advances in pancreatic organoid and organoid-on-a-chip technologies, focusing on their applications in pancreatic disease modeling, therapeutic screening, and potential relevance to personalized treatment. MAIN TEXT: This review discusses the construction of pancreatic organoids and pancreatic organoid-on-a-chip platforms, including key culture parameters and practical strategies for model establishment. The applications of pancreatic organoids in modeling pancreatic cancer, diabetes, pancreatitis, and cystic fibrosis are reviewed. In addition, the role of patient-derived organoids in therapeutic screening and their potential integration into personalized treatment workflows are evaluated. The enabling role of artificial intelligence in pancreatic organoid research is also discussed, followed by an overview of the current challenges and future perspectives. CONCLUSION: Pancreatic organoid-based platforms are promising tools for pancreatic disease modeling and therapeutic evaluation. Addressing the current limitations of cellular complexity, vascularization, reproducibility, and scalability is essential for expanding their research and clinical utility.
Resveratrol derivative restores macrophage cholesterol homeostasis via stabilizing xanthine oxidoreductase in hepatocellular carcinoma.
Liang G, Zeng L, Huang X … +11 more , Ma Q, Wang H, Wang Y, Liu T, Tu X, Peng J, Huang H, Liu W, Ke P, Yan J, He M
J Transl Med · 2026 Jun · PMID 42321758 · Full text
BACKGROUND: Tumor-associated macrophages (TAMs) are key determinants of the immunosuppressive microenvironment in hepatocellular carcinoma (HCC) and critically influence the efficacy of immunotherapy. However, how metabo...
BACKGROUND: Tumor-associated macrophages (TAMs) are key determinants of the immunosuppressive microenvironment in hepatocellular carcinoma (HCC) and critically influence the efficacy of immunotherapy. However, how metabolic regulators shape TAM immunophenotypes and subsequent CD8⁺ T cell dysfunction in HCC remains incompletely understood. METHODS: Single-cell RNA sequencing data and primary tumor samples from patients with HCC were used to characterize xanthine oxidoreductase (XOR) expression on TAMs, and to clarify the underlying mechanisms mediating the effects of XOR⁺ monocytes/macrophages on CD8⁺ T cells. An in-house small-molecule library was screened to identify compounds capable of modulating XOR activity, followed by mechanistic and therapeutic validation in vivo. RESULTS: We identified a marked downregulation of XOR expression in TAMs within HCC tumors, which was significantly associated with poor clinical outcomes. Mechanistically, loss of XOR disrupted PPARγ signaling and cholesterol homeostasis in macrophages, driving their polarization toward an alternatively activated, immunosuppressive M2 phenotype. XOR-deficient TAMs exhibited an impaired capacity to support CD8⁺ T cell activation through enhancing PD-L1 expression, thereby facilitating tumor progression. Notably, a resveratrol derivative, Res616, directly bound to and stabilized the XOR protein, restoring cholesterol metabolic balance and reversing the immunosuppressive phenotype of TAMs. Therapeutically, targeting XOR with Res616 significantly enhanced intratumoral CD8⁺ T cell responses and synergized with anti-PD-L1 therapy to suppress tumor growth in murine HCC models. CONCLUSIONS: Our study identified XOR as a pivotal metabolic checkpoint governing TAM-mediated immunosuppression in HCC. Pharmacological stabilization of XOR to restore macrophage cholesterol homeostasis represented a previously unrecognized strategy to remodel the tumor immune microenvironment and improve the efficacy of immune checkpoint blockade.
Transcriptional and functional profiling reveals unique activation of Adapter CAR T cells in acute myeloid leukemia.
Knelangen N, Bader U, Maniaki E … +3 more , Engels B, Gattinoni L, Mittelstaet J
J Transl Med · 2026 Jun · PMID 42316369 · Full text
BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has shown great promise in treating malignant diseases, yet its efficacy is often limited by challenges such as controllability and the lack of tumor-specific an...
BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has shown great promise in treating malignant diseases, yet its efficacy is often limited by challenges such as controllability and the lack of tumor-specific antigens. Adapter CAR (AdCAR) T cells address these limitations by redirecting T cell activity through adapter molecules rather than direct interaction with tumor-associated antigens, offering an on-/off- switch mechanism and the potential for multitargeting. While functionality of AdCAR T cells has been demonstrated in various models, the underlying AdCAR T cell response to differing adapter concentration and its comparison to conventional CAR T cells remain poorly characterized. METHODS: In this study, we systematically examined adapter-dependent AdCAR T cell responses using functional assays and single-cell RNA sequencing in an acute myeloid leukemia model. RESULTS: Adapter concentration was found to determine AdCAR T cell activation dynamics, transcriptional states and metabolic reprogramming. At low adapter concentrations, an interferon-responsive state was observed, while high concentrations induced strong cytolytic activity, cytokine secretion, and metabolic shifts toward glycolysis and oxidative phosphorylation. Importantly, increasing adapter concentrations enhanced tumor control of sub-optimally activated AdCAR T cells, demonstrating the platform's tunability. A hallmark gene signature was identified across different adapters and target cells, comprising the interferon-responsive gene MX1 and activation-associated genes including ENO1, HSP90AB1, and RRM2. CONCLUSIONS: Our findings provide a mechanistic framework for tuning AdCAR T cell responses and offer critical insights for optimizing adapter dosing to enhance the safety and efficacy of tunable CAR T cell therapies.
Functional consistency and molecular evolution: a comprehensive characterization of primary endometrial cancer-associated fibroblasts during in vitro expansion.
Bao L, Wang P, Wang D … +12 more , Li X, Zhang H, Wan X, Yuan R, Xie N, Lei L, Cheng Q, Lei X, Cao X, Dai H, Zheng T, Jiang H
J Transl Med · 2026 Jun · PMID 42316290 · Full text
BACKGROUND: Cancer-associated fibroblasts (CAFs) are critical components of the tumor microenvironment in endometrial cancer (EC). Primary isolation and culture of CAFs serve as the standard method for investigating thei...
BACKGROUND: Cancer-associated fibroblasts (CAFs) are critical components of the tumor microenvironment in endometrial cancer (EC). Primary isolation and culture of CAFs serve as the standard method for investigating their biological roles. However, it remains unclear whether prolonged in vitro culture alters the intrinsic properties of CAFs, potentially affecting experimental reproducibility. This study aims to evaluate the phenotypic and transcriptomic evolution of primary EC-derived CAFs across different passages. METHODS: CAFs were isolated from human EC tissues using enzymatic digestion and differential adherence. Cells at passages 1 (P1), 5 (P5), and 10 (P10) were compared. Biological phenotypes, including proliferation, migration, apoptosis, senescence, and cytokine secretion, were assessed. The effects of CAF-conditioned medium (CM) on the proliferation and invasion of EC cell lines (ISHIKAWA and HEC-1 A) were evaluated. Furthermore, RNA sequencing (RNA-seq) was performed to uncover molecular alterations, followed by functional enrichment and subtype analyses. Additional validation experiments, including ROS detection, NF-κB activation analysis, H₂O₂-induced oxidative stress modeling, and NAC or TPCA-1 intervention, were conducted to investigate the mechanism underlying passage-associated inflammatory drift. RESULTS: CAFs maintained a consistent spindle-shaped morphology and expression of specific markers (Vimentin/FAP) from P1 to P10. Functional assays demonstrated no significant differences in proliferation, migration, or senescence rates across passages. Crucially, CAFs at all passages exhibited comparable efficacy in promoting the proliferation, migration, and invasion of EC cells. However, transcriptomic profiling revealed profound reprogramming, with 1,300 core genes differentially expressed in P5/P10 compared to P1. While pathways related to extracellular matrix remodeling (myCAF signature) remained stable, establishing the molecular basis for sustained invasion support, passaged CAFs progressively exhibited reduced antigen-presenting signatures and acquired a pro-inflammatory iCAF-like phenotype. Mechanistically, late-passage CAFs showed increased ROS accumulation, enhanced P65 phosphorylation and nuclear translocation, and upregulated inflammatory mediators, including IL6, CXCL1, CXCL2, and CCL2. H₂O₂ treatment partially mimicked this inflammatory phenotype in P1 CAFs, whereas NAC or TPCA-1 attenuated inflammatory activation in P10 CAFs. CONCLUSIONS: Primary endometrial CAFs retain core tumor-supporting phenotypes and myofibroblastic characteristics up to passage 10, validating their utility as reliable in vitro models for invasion and metastasis studies. However, high-passage CAFs exhibit a culture-associated inflammatory transcriptional drift driven, at least in part, by ROS/NF-κB activation, together with reduced immunogenic features. These findings provide essential guidelines for the standardization of CAF-based research models and caution against using high-passage CAFs for immune-interaction or inflammation-related studies.
Chronic proton pump inhibitor exposure aggravates intestinal injury by impairing intestinal stem cell self-renewal through the microbiota-7-ketolithocholic acid Axis.
Wang X, Cheng L, Yin K … +3 more , Wang B, Yan X, Chen S
J Transl Med · 2026 Jun · PMID 42316284 · Full text
BACKGROUND: Long-term proton pump inhibitor (PPI) use is associated with increased intestinal disease risk, but its damaging mechanisms remain unclear. METHODS: Mice were administered rabeprazole (Rab) for 4 weeks before...
BACKGROUND: Long-term proton pump inhibitor (PPI) use is associated with increased intestinal disease risk, but its damaging mechanisms remain unclear. METHODS: Mice were administered rabeprazole (Rab) for 4 weeks before dextran sulfate sodium (DSS) or ionizing radiation (IR) injury. We employed RNA sequencing, metabolomics, and metagenomics, evaluated intestinal stem cell (ISC) function, and used organoids for validation. RESULTS: Long-term Rab induced small intestinal mucosal injury and exacerbated DSS/IR-induced damage, manifesting as crypt/villus atrophy and reduced ISC numbers. Mechanistically, Rab downregulated the Wnt pathway and impaired mucosal defense and regeneration. Microbiota involvement was indicated by fecal transplantation. Integrated metagenomic and metabolomic analyses revealed that Rab induced intestinal dysbiosis and reduced ileal bile acids, particularly 7-ketolithocholic acid (7KLCA) and chenodeoxycholic acid (CDCA). Faecalibaculum rodentium supplementation restored ISC self-renewal by converting CDCA to 7KLCA. In vitro, 7KLCA activated Wnt signaling to rescue Rab-induced stem cell impairment. In vivo, both 7KLCA and Gly-β-MCA (intestinal FXR antagonists) suppressed the FXR-FGF15 axis, restored the expression of hepatic bile acid synthesis enzymes, and promoted epithelial repair, thereby mitigating DSS-induced injury. CONCLUSIONS: Chronic PPI use impairs ISC self-renewal by disrupting the microbiota-7KLCA-Wnt axis. F. rodentium or 7KLCA supplementation ameliorates PPI-induced effects, highlighting a microbe-metabolite axis as a pivotal mechanism and potential therapies for PPI-associated intestinal damage.
IL-1β/CXCL12 signalling orchestrates adipocyte-pancreatic neuroendocrine tumor crosstalk.
Oldani M, Grassi ES, Gaudenzi G … +7 more , Rybinska I, Carra S, Massardi E, Fazio N, Caraglia M, Persani L, Vitale G
J Transl Med · 2026 Jun · PMID 42316277 · Full text
BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms belonging to the broader group of neuroendocrine neoplasms. Epidemiological evidence indicates that visceral obesity is associated with both an in...
BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms belonging to the broader group of neuroendocrine neoplasms. Epidemiological evidence indicates that visceral obesity is associated with both an increased incidence of PanNETs and unfavorable clinicopathological features. However, the mechanisms underlying adipocyte-PanNETs interactions remain poorly understood. METHODS: Here, we investigated the crosstalk between adipocytes and PanNET cells (BON-1 and QGP-1 cell lines) using indirect co-culture systems and conditioned media derived from differentiated 3T3-L1 adipocytes or PanNET cells. RESULTS: Our results demonstrate that PanNET cells induce adipocyte reprogramming toward a cancer-associated adipocyte (CAA) phenotype, characterized by lipid depletion and downregulation of adipogenic markers, including Pparg, Fabp4, Hsl, and Atgl. We identified PanNET-derived interleukin-1β (IL-1β) as a key driver of adipocyte conversion into CAAs. This process was accompanied by increased secretion of the chemokine CXCL12 from CAAs, which in turn appeared to enhance PanNET cell proliferation and IL-1β release, thereby establishing a positive bidirectional crosstalk consistent with a feedback-like mechanism between CXCL12 and IL-1β in CAAs and PanNET cells, respectively. Indeed, pharmacological disruption of this axis using AMD3100, a CXCR4 antagonist, significantly reduced both IL-1β and CXCL12 secretion, prevented adipocyte reprogramming, and suppressed tumor cell proliferation. Comparable effects were observed following incubation of PanNET-adipocyte co-cultures with canakinumab, an IL-1β pathway inhibitor. CONCLUSION: Collectively, these findings identify IL-1β and CXCL12 as potential critical mediators of the inflammatory crosstalk between adipocytes and PanNET cells. Targeting this signalling axis may therefore represent a promising therapeutic strategy for PanNETs.
Molecular characterisation of telitacicept response phenotypes in systemic lupus erythematosus: an exploratory integrated transcriptome and B-cell receptor repertoire profiling study.
Chen M, Wang W, Cheng Y … +1 more , Tang Y
J Transl Med · 2026 Jun · PMID 42316250 · Full text
BACKGROUND: Telitacicept, a dual BAFF/APRIL inhibitor, has shown clinical efficacy in systemic lupus erythematosus (SLE), but the underlying molecular mechanisms remain incompletely understood. METHODS: We performed an i...
BACKGROUND: Telitacicept, a dual BAFF/APRIL inhibitor, has shown clinical efficacy in systemic lupus erythematosus (SLE), but the underlying molecular mechanisms remain incompletely understood. METHODS: We performed an integrative longitudinal study in ten patients with SLE before and after telitacicept treatment, alongside ten healthy controls. Paired transcriptome RNA sequencing and dedicated B-cell receptor (BCR) sequencing and repertoire analysis were integrated with serial clinical phenotyping including SLEDAI-2 K, anti-dsDNA antibodies, and complement C3/C4 levels over 12 months of follow-up. Differential expression analysis, pathway enrichment, cell deconvolution, and BCR clonal tracking were conducted. RESULTS: Telitacicept treatment was associated with reduced B-cell clonal diversity and decreased estimated plasma cell abundance, alongside partial reconstitution of naive B cells. Downregulation of PI3K-Akt and NF-κB pathway genes was observed. BCR repertoire analysis suggested loss of 58.7% of clones expressing IGHV4-34, IGHV3-30, and IGHV1-46, which correlated positively with baseline disease activity scores. An unexpected upregulation of interferon-stimulated genes (ISGs) was noted post-treatment, a signature not observed in independent cohorts receiving standard-of-care therapies. Exploratory subgrouping based on ISG dynamics suggested potential differences in clinical trajectory: the ISG-upregulated subgroup showed a more pronounced initial reduction in SLEDAI-2 K scores at three months, followed by a subsequent increase in disease activity scores during extended follow-up, whereas the non-upregulated subgroup maintained relatively stable scores. CONCLUSIONS: These preliminary findings suggest that telitacicept may remodel the B-cell repertoire while concurrently modulating interferon pathways in SLE. The observed ISG upregulation generates hypotheses regarding post-treatment immune dynamics that warrant validation in larger, independent cohorts.
Critical evaluation of "Diffuse reflectance spectroscopy for enhanced diagnostic precision in breast cancer".
Bibi Z, Ali K
J Transl Med · 2026 Jun · PMID 42316216 · Full text
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Patient-specific lung cancer tumoroids recapitulate the tumor microenvironments for functional evaluation of therapeutic responses and immune-stromal interactions.
Ko YR, Park CW, Kim J … +7 more , Jung DJ, Kim SM, Park HS, Ahn B, Hwang HS, Sung CO, Jang SJ
J Transl Med · 2026 Jun · PMID 42316214 · Full text
BACKGROUND: Tumor heterogeneity and the complexity of the tumor microenvironment (TME) drive therapeutic resistance in lung cancer, highlighting the critical need for experimental models that faithfully recapitulate tumo...
BACKGROUND: Tumor heterogeneity and the complexity of the tumor microenvironment (TME) drive therapeutic resistance in lung cancer, highlighting the critical need for experimental models that faithfully recapitulate tumor-stroma-immune interactions. METHODS: We developed patient-specific lung cancer tumoroid (LCT) models by integrating lung cancer organoids (LCOs), cancer-associated fibroblasts (CAFs) and immune cells isolated from single tumor tissue sources using a modular, transwell-based culture platform. The model supports cryopreservation and reproducible reconstruction of cellular components. Multimodal assessments, including histological characterization, dose-response pharmacologic profiling, immune profiling, and transcriptomic analyses, were performed across diverse co-culture configurations to evaluate patient-specific TME features and treatment-associated responses. RESULTS: The LCT models successfully recapitulated key structural and cellular features of native TMEs, demonstrating high reproducibility across patient samples. Functional analyses revealed tumor-intrinsic heterogeneity in responses to chemotherapy and chemo-immunotherapy. CAF integration altered therapeutic responses and was associated with reduced immune activation and cytotoxic efficacy in selected models, suggesting stromal contributions to treatment resistance. Transcriptomic analyses showed that reconstructed TMEs preserved patient-specific stromal and immune programs associated with therapeutic responsiveness, including transcriptional features linked to clinical outcomes in independent immunotherapy-treated cohorts. CONCLUSIONS: This patient-specific LCT model provides a scalable and translationally relevant approach for the ex vivo reconstruction of native TMEs, facilitating the functional interrogation of tumor-stroma-immune interactions. By capturing heterogeneous stromal responses, this platform offers a valuable tool for investigating therapeutic resistance and supports the further development of precision immune-oncology and patient-tailored therapeutic strategies in lung cancer.
HIF-1α attenuates ferroptosis-associated dermal fibroblast senescence via modulation of NF-κB-DPP4 signaling.
Ng SC, Kao SW, Chen CJ … +6 more , Lin SZ, Hsieh DJ, Kuo CH, Lin KH, Huang CY, Kuo WW
J Transl Med · 2026 Jun · PMID 42316209 · Full text
BACKGROUNDS: Skin aging is characterized by progressive structural and functional decline driven in part by chronic oxidative stress. Ferroptosis-associated processes have been increasingly implicated in cellular senesce...
BACKGROUNDS: Skin aging is characterized by progressive structural and functional decline driven in part by chronic oxidative stress. Ferroptosis-associated processes have been increasingly implicated in cellular senescence and are linked to dipeptidyl peptidase-4 (DPP4). Although hypoxia-inducible factor-1α (HIF-1α) is essential for skin homeostasis, its role in dermal fibroblast aging remains incompletely understood. This study aimed to determine whether HIF-1α modulates ferroptosis-associated senescence in human dermal fibroblasts (HDFs) and to explore the involvement of NF-κB-DPP4 signaling. METHODS: HIF-1α expression was examined in aged HDFs and sun-exposed human skin. Transcriptomic profiling was performed to assess pathways associated with hypoxia in aging models. Pharmacological modulators of ferroptosis, DPP4, and HIF-1α were applied in vitro to evaluate effects on senescence and ferroptotic markers. NF-κB activity and DPP4 transcription were analyzed using molecular assays. Potential in vivo relevance was evaluated in aged mice treated with a HIF-1α activator or a ferroptosis inhibitor. RESULTS: HIF-1α expression was reduced in aged HDFs and photoaged skin, and its depletion accelerated cellular senescence. Transcriptomic analysis suggested downregulation of ferroptosis-related pathways under hypoxic conditions. Induction of ferroptosis-associated stress promoted senescence phenotypes in HDFs, whereas hypoxia-induced HIF-1α activation attenuated these effects. Mechanistically, NF-κB functioned as a transcriptional regulator of DPP4, and hypoxia was associated with reduced NF-κB activity, decreased DPP4 expression, and lower secretion of soluble DPP4 (sDPP4). Inhibition of DPP4 mitigated ferroptosis-associated senescence and restrained sDPP4-mediated paracrine propagation to neighboring young fibroblasts. In aged mice, topical treatment with a HIF-1α activator or a ferroptosis inhibitor was associated with improved dermal structure and reduced senescence markers. CONCLUSION: These findings support a model in which HIF-1α is associated with suppression of NF-κB-dependent DPP4 expression and attenuation of ferroptosis-associated fibroblast senescence. Targeting the HIF-1α/NF-κB/DPP4 axis may represent a potential strategy for mitigating skin aging.
Crosstalk In: crosstalk-aware inference of tumor microenvironment cell infiltration.
Yi Q, Yuan J, Ye Z … +2 more , Xu P, Liu W
J Transl Med · 2026 Jun · PMID 42316201 · Full text
BACKGROUND: The tumor microenvironment (TME) is a complex ecosystem whose cellular composition and interactions shape tumor progression, therapeutic response, and patient prognosis. However, most bulk deconvolution metho...
BACKGROUND: The tumor microenvironment (TME) is a complex ecosystem whose cellular composition and interactions shape tumor progression, therapeutic response, and patient prognosis. However, most bulk deconvolution methods infer cell-type composition while treating cell types independently. METHODS: In this paper, we develop CrosstalkIn, a crosstalk-aware bulk deconvolution framework that constructs patient-specific cell-cell networks by integrating Gene Ontology (GO)-based functional similarity and protein-protein interaction (PPI)-based molecular relationships. A modified random walk with restart algorithm is then applied to calculate cell Infiltration Scores (InScores). RESULTS: Benchmark results on two flow-cytometry-validated cohorts demonstrate that CrosstalkIn achieves superior deconvolution performance, with the largest or second-largest Spearman correlations for most evaluated cell types. In lower-grade glioma, CrosstalkIn-derived InScores identify survival-associated cell types, generate accurate prognostic risk scores, and stratify patients into distinct survival groups. Across multiple adenocarcinoma cohorts, the risk score shows consistent prognostic value, particularly in advanced-stage patients. In melanoma, CrosstalkIn improves immunotherapy response prediction and identifies biologically interpretable cell-type biomarkers. CONCLUSION: CrosstalkIn provides a robust framework for crosstalk-aware inference of TME cell infiltration from bulk transcriptomic data and supports cancer prognosis and immunotherapy response prediction.
S-propargyl-cysteine remodels the HCC microenvironment and potentiates anti-PD-1 therapy through CSE/HS-linked vascular and immune reprogramming.
Liang Y, Zhong D, Yan H … +5 more , Su Y, Chen Y, Wang M, Zhu Y, Yang Q
J Transl Med · 2026 Jun · PMID 42316187 · Full text
BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by aberrant angiogenesis and an immunosuppressive tumor microenvironment, both of which limit durable responses to PD-1 blockade. Strategies that concurrently t...
BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by aberrant angiogenesis and an immunosuppressive tumor microenvironment, both of which limit durable responses to PD-1 blockade. Strategies that concurrently target vascular dysfunction and immune inhibition may improve therapeutic efficacy. METHODS: The interaction between S-propargyl-cysteine (SPRC) and cystathionine-gamma-lyase (CSE) was assessed by surface plasmon resonance. In human umbilical vein endothelial cells, NF-κB p65 and STAT3 phosphorylation, VEGFA expression, extracellular HS production, CSE enzymatic activity, and tube formation were evaluated. In HepG2 and activated Jurkat-cell co-cultures, PD-L1 expression, T-cell phenotypes, and granzyme B secretion were analyzed. H3K27me3 enrichment at RELA and STAT3 was examined by ChIP-qPCR. Antitumor efficacy was assessed in an HCC mouse model treated with anti-PD-1 alone or in combination with SPRC. Tumor tissues were further analyzed for intratumoral H₂S levels, CSE enzymatic activity, NF-κB/STAT3 activation, VEGFA and PD-L1 expression, CD31-associated vascular density, immune-cell infiltration, metabolomic remodeling, and oxidative-stress status. RESULTS: SPRC bound recombinant CSE with nanomolar affinity and enhanced CSE-dependent HS generation and enzymatic activity. In endothelial cells, SPRC reduced NF-κB p65 and STAT3 phosphorylation, decreased VEGFA expression, and impaired tube formation, whereas these effects were attenuated by CSE knockdown. In co-culture, SPRC reduced PD-L1 expression on HepG2 cells and promoted a more cytotoxic T-cell phenotype, as indicated by increased CD8α, reduced FoxP3, and elevated granzyme B secretion. Rescue experiments showed that constitutively active STAT3 restored PD-L1 expression despite SPRC treatment, whereas p65 overexpression reversed SPRC-mediated suppression of VEGFA expression and endothelial tube formation. SPRC also increased H3K27me3 enrichment at the RELA and STAT3 promoters. In vivo, SPRC enhanced the antitumor efficacy of PD-1 blockade, increased intratumoral CD8⁺ T-cell infiltration, decreased Treg abundance, and reduced CD31-associated vascular density. Mechanistically, SPRC plus anti-PD-1 increased intratumoral H₂S levels and CSE enzymatic activity, suppressed NF-κB p65 and STAT3 phosphorylation, and decreased VEGFA and PD-L1 expression in tumor tissues. Metabolomic profiling further linked an amino-acid-centered metabolic module, particularly the arginine-ornithine-citrulline axis, to immune and vascular remodeling, accompanied by reduced MDA and increased SOD activity. CONCLUSIONS: SPRC activates a functional CSE/HS-linked program that suppresses NF-κB/STAT3 signaling, inhibits angiogenesis, alleviates PD-L1-associated immune suppression, and enhances the efficacy of PD-1 blockade in HCC. These findings support SPRC as a promising adjunct strategy for microenvironment-targeted immunotherapy in HCC.
Puerarin ameliorates obesity-induced spermatogenic dysfunction by targeting GRP78/StAR to increase testosterone synthesis.
Pan Y, Li Y, Huang K … +9 more , Huang Q, Fu Z, Wu H, Yang J, Cai Y, Qian W, Cao X, Lei X, Xue L
J Transl Med · 2026 Jun · PMID 42316183 · Full text
BACKGROUND: Testosterone synthesis dysfunction caused by obesity is a major contributor to male infertility, but effective therapeutic options remain limited. Puerarin (Pue), a bioactive compound from Pueraria lobata, ha...
BACKGROUND: Testosterone synthesis dysfunction caused by obesity is a major contributor to male infertility, but effective therapeutic options remain limited. Puerarin (Pue), a bioactive compound from Pueraria lobata, has lipid-lowering and reproductive-protective properties. This study aimed to investigate the mechanisms by which Pue ameliorates obesity-associated spermatogenic impairment. METHODS: A high-fat diet (HFD) mouse model was used to assess the effects of Pue supplementation on lipid metabolism, testosterone levels and spermatogenesis. Network pharmacology, transcriptomics, and activity-based protein profiling (ABPP) analyses were performed to explore potential pathways and protein targets. In addition, pull-down assays, immunofluorescence, and cellular thermal shift assays (CETSA) were used to validate target engagement, and the role of the identified target was further tested in palmitic acid (PA)-induced TM3 cells by using protein target inhibitors and protein target overexpression to verify the ability of Pue to ameliorate obesity-related testosterone synthesis dysfunction. RESULTS: Pue supplementation markedly alleviated obesity-induced metabolic disorders by reducing body weight gain, adiposity, and hepatic lipid deposition while improving serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels. Pue supplementation preserved testicular and epididymal morphology and significantly increased the serum testosterone level, sperm count, and sperm motility. Transcriptomic analysis revealed that Pue restored the expression of steroidogenic acute regulatory protein (StAR), cytochrome P450 family 11 subfamily A member 1 (CYP11A1), 3β-hydroxysteroid dehydrogenase (3β-HSD), and cytochrome P450 family 17 subfamily A member 1 (CYP17A1). Pull-down assays, molecular docking, and CETSAs revealed that glucose-regulated protein 78 (GRP78) is a Pue-binding target, with Pue forming hydrogen bonds at the TYR-65 residue. Coimmunoprecipitation (Co-IP) and colocalization assays verified the specific GRP78-StAR interaction. Pue binding enhanced the chaperone activity of GRP78, stabilized StAR and upregulated its expression. The inhibition of GRP78 reduced StAR expression and testosterone secretion in TM3 cells, whereas Pue supplementation reversed these effects, and GRP78 overexpression further enhanced the therapeutic effect of Pue. CONCLUSION: Pueraria root alleviates obesity-induced spermatogenic dysfunction by improving lipid metabolism, upregulating the expression of key testosterone enzymes, and promoting testosterone synthesis through the targeting of GRP78 by StAR expression. These findings reveal a novel mechanism through which Pue restores androgen biosynthesis and provide a scientific basis for the development of Pueraria-derived interventions for obesity-associated male infertility.
Computational prediction of TCR cross-reactivity: principles, challenges and translational opportunities.
Li W, Pan Y, Wu X … +3 more , Song Y, Wang Y, Xie L
J Transl Med · 2026 Jun · PMID 42316179 · Full text
T-cell receptor (TCR) cross-reactivity, whereby a single TCR recognizes multiple peptide-MHC (pMHC) ligands, is essential for immune surveillance but also represents a major safety challenge for TCR-based therapeutics be...
T-cell receptor (TCR) cross-reactivity, whereby a single TCR recognizes multiple peptide-MHC (pMHC) ligands, is essential for immune surveillance but also represents a major safety challenge for TCR-based therapeutics because of severe off-target toxicities. Rapid advances in immune-repertoire sequencing, structural biology, and immunopeptidomics have accelerated computational efforts to characterize cross-reactive recognition at scale. However, most existing methods are adapted from conventional TCR-pMHC specificity prediction and remain insufficiently aligned with the one-to-many, structurally plastic, and context-dependent nature of cross-reactivity. Here, we review the main data resources supporting TCR cross-reactivity modeling, including sequence- and structure-centric databases, and highlight persistent limitations, such as scarce explicitly annotated cross-reactive TCRs, strong biases toward viral epitopes and common HLA alleles, limited paired αβ-chain information, and a lack of rigorously validated negative examples. We then compare the major computational paradigms-sequence-based, structure-based, machine-learning, and multimodal approaches-with emphasis on their respective strengths and limitations in interpretability, generalization, and scalability. Finally, we discuss emerging translational applications and outline key priorities for the field, including dedicated datasets, rigorous benchmarking, and biologically grounded multimodal models to enable safer and more clinically actionable TCR-based immunotherapies.
Gut dysbiosis associated with neonatal respiratory distress syndrome and biological plausibility of disease-specific probiotic intervention: a translational study.
Seo E, Kim SH, Kwak MJ … +7 more , Hwang JK, Mustafa G, Chang YS, Hoh JK, Jeon BH, Park HK, Kim Y
J Transl Med · 2026 Jun · PMID 42316154 · Full text
BACKGROUND: Neonatal respiratory distress syndrome (RDS) is among the most prevalent morbidities in late preterm and term infants. Although the gut-lung axis has been implicated in neonatal respiratory disease, the relat...
BACKGROUND: Neonatal respiratory distress syndrome (RDS) is among the most prevalent morbidities in late preterm and term infants. Although the gut-lung axis has been implicated in neonatal respiratory disease, the relationship between RDS and early gut microbiome composition remains poorly characterized. This study aimed to characterize gut microbiome alterations associated with RDS and surfactant replacement therapy (SRT), and to evaluate the biological plausibility of a disease-specific probiotic intervention. METHODS: Two complementary cohorts were prospectively enrolled. In the clinical observational cohort (n = 45), fecal samples collected within 48 h of birth were analyzed by Nanopore 16S rRNA sequencing across three groups: infants without RDS (control group, n = 25), infants with RDS who did not receive SRT (RDS(S-) group, n = 7), and infants with RDS who received SRT (RDS(S+) group, n = 13). In the probiotic discovery cohort (n = 40), gut microbiota of infants without RDS (CON group, n = 17) and infants with RDS (RDS group, n = 23) were characterized by metagenomic sequencing and culturomics. Candidate probiotic strains were evaluated in a fermenter for intestinal microbiota model (FIMM) and a fecal microbiota transplantation (FMT) mouse model. RESULTS: The RDS(S-) group exhibited depletion of beneficial taxa including Bifidobacterium and Lacticaseibacillus and enrichment of opportunistic pathogens including Enterococcus and Staphylococcus. Following SRT, gut microbial profiles partially shifted toward those of the control group. Limosilactobacillus fermentum SLAM_LAF05 and Bifidobacterium longum SLAM_BIL02 were identified as CON-enriched candidate probiotic strains through direct microbiome comparison and selected based on superior acid and bile tolerance and adhesion capacity. In the FIMM model, probiotic supplementation increased microbial diversity and suppressed opportunistic pathogens. In the FMT mouse model, probiotic supplementation was associated with upregulation of ZO-1, MUC2, and Reg3g, reduction of fecal calprotectin, and restoration of serum IgG levels. CONCLUSIONS: This study provides an early translational characterization of RDS-associated gut dysbiosis and its partial resolution following SRT, and establishes proof-of-concept for a disease-specific probiotic approach. These findings offer a new perspective on the interplay between gut microbial dynamics and the early postnatal respiratory course, and provide a basis for future investigations into microbiota-targeted strategies in neonates with RDS.
SP-printer: reconstruction of tumor stage-specific microenvironments via phenotype-integrated spatial transcriptomics.
Deng W, Shi Y, Tang H
J Transl Med · 2026 Jun · PMID 42310765 · Full text
BACKGROUND: Spatial transcriptomics (ST) technologies have rapidly advanced the investigation of tumor microenvironment (TME) mechanisms by enabling high-resolution mapping of mRNA molecules within their native spatial c...
BACKGROUND: Spatial transcriptomics (ST) technologies have rapidly advanced the investigation of tumor microenvironment (TME) mechanisms by enabling high-resolution mapping of mRNA molecules within their native spatial context. However, existing methods often overlook phenotypic indices like malignancy status, limiting their interpretability within the tumor microenvironment. METHODS: This work proposes SP-printer (Spatial-Phenotype printer), a flexible integrating approach that integrates phenotypic and spatial data to quantify stage-specific malignancy levels at each spot. SP-printer first identifies stage-specific metagenes from bulk RNA-seq datasets by using a S-score strategy. These metagenes are then projected onto ST data at pixel level via an information-enhanced mapping strategy, generating spatially resolved stage phenotypes. Finally, the pixel-level mappings are aggregated to spot resolution, enabling compatibility with standard ST workflows and supporting downstream analyses. RESULTS: SP-printer outperforms state-of-the-art methods in identifying malignant regions across diverse tumor tissues. Specifically, we identified early microenvironment diagnostic markers for primary liver cancer and liver metastasis and evaluated the effects of seven drugs on the tumor microenvironment, providing a comprehensive assessment of their therapeutic potential. CONCLUSIONS: SP-printer offers a unified framework to dissect the tumor spatial microenvironment and bridge the gap between cellular context and phenotypic outcomes, thereby enhancing the precision of tumor microenvironment analysis and facilitating informed clinical decision-making.
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