Organic room-temperature phosphorescence (RTP) materials hold great promise as bioimaging agents due to their long-lived emission and high signal-to-background ratios. However, their application in physiological environments is often hampered by water-induced quenching. Herein, we report a ternary-component nanoengineering strategy featuring a precisely engineered hydrophobic-hydrophilic architecture that enables bright, color-tunable, and long-lived RTP in aqueous media. The optimized 1,2‑PhCS@PLA nanoparticles achieve an ultralong phosphorescence lifetime of 1.04 s, the longest reported for aqueous organic RTP systems to date, and retain robust afterglow under physiological conditions with persistent RTP exceeding 12 s at 310 K (close to body temperature). This outstanding performance is enabled by a multifunctional hydrophobic layer that (1) protects triplet excitons from water, (2) suppresses nonradiative decay through matrix rigidity, and (3) allows dynamic oxygen responsiveness via its porous nature. These features enable quantitative in vitro hypoxia detection and high-contrast afterglow imaging of tumor hypoxia in living mice, achieving a signal-to-background ratio up to 221. This work establishes a foundation for advanced phosphorescent biosensors and biomedical imaging applications.

Fibrosis resulting from metabolic-associated steatohepatitis (MASH) is increasingly recognized as the predominant form of liver fibrosis. Although the activation of hepatic stellate cells (HSCs) is essential for liver fibrosis, the mechanisms underlying HSC activation in MASH remain inadequately understood. Integrated analysis of large-scale single-cell and single-nucleus RNA sequencing data from human healthy and fibrosis samples reveals a distinct subpopulation of HSCs in MASH. AREL1 is a characteristic gene of this subpopulation and is uniquely upregulated in MASH-related fibrosis. HSC-specific knockout of Arel1 markedly attenuates liver fibrosis in MASH model male mice. Mechanistically, AREL1 is regulated by cholesterol and facilitates HSC activation through the AREL1-ILK axis, subsequently activating the PI3K-AKT signaling pathway. Moreover, therapeutic knockdown of Arel1 using vitamin A-modified lipid nanoparticles markedly ameliorates MASH-related liver fibrosis. Here, we show a unique mechanism underlying HSC activation in MASH-driven fibrosis and present the targeted knockdown of AREL1 in HSCs as a therapeutic avenue.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced malignancies; however, their efficacy in solid tumors remains limited by therapy resistance. This resistance arises from the metabolic reprogramming of immune cells in the tumor microenvironment (TME), a metabolic 'cage' where immune and cancer cells compete for nutrients. Immune effector cells succumb to metabolic exhaustion amid nutrient competition, whereas immunosuppressive cells augment inhibitory functions via metabolic adaptation, collectively mediating tumor immune evasion. This review systematically delineates the metabolic reprogramming features of immune cells in the TME, dissects the molecular mechanisms governing ICI resistance, and summarizes combination strategies targeting metabolic pathways to reverse resistance, providing theoretical and translational insights for optimizing cancer immunotherapy.

Hepatocellular carcinoma (HCC) is a common malignancy and a leading cause of cancer-related mortality. Current guidelines and staging systems provide coarse categories, but often miss within-stage heterogeneity and the clinical context in electronic medical records (EMRs). We present HCC-STAR (Hepatocellular Carcinoma Staging, Treatment And pRognosis), a clinically aligned large language model that reads routine EMR narratives and jointly outputs risk score-based staging, ranked guideline-consistent treatments with evidence-based rationales, and individualized survival estimates. We curated about 30,000 HCC cases from SEER and expanded them into EMR-style narrative training data using a clinician-validated, prompt-based augmentation workflow. On this corpus, we developed a knowledge-aligned reasoning framework optimized with a step-verifiable composite reward, moving beyond text-level memorization of clinical guidelines. In a multi-center cohort of 6,668 patients from 12 hospitals in China, HCC-STAR achieved state-of-the-art performance in treatment recommendation and risk stratification compared with clinical guidelines and competitive models, including GPT-5 and Gemini-2.5 Pro. Hypothetical overall-survival analysis showed a median survival of 51 months under adherence to HCC-STAR recommendations, compared with 29 and 32 months under BCLC and CNLC. In clinician-centric evaluations, blinded hepatobiliary specialists rated HCC-STAR's reasoning and evidence-based justifications as trustworthy. The model surpassed resident and attending physicians in treatment accuracy and helped physicians make more accurate decisions faster when used as an assistant. These findings support HCC-STAR as a reliable and verifiable decision-support system for risk stratification and precision therapy in HCC.

The afterglow luminescence imaging technology, as an emerging tool for precise tumor diagnosis and treatment, provides intraoperative navigation and postoperative monitoring methods for surgeons. From a clinical perspective, this article systematically reviews the current application status, clinical translation opportunities, and challenges of afterglow luminescent materials in tumor resection surgeries. From the perspective of a surgeon, it emphasizes the future development needs and calls for the establishment of a cross-disciplinary collaboration platform to jointly promote the application of afterglow luminescence imaging from the laboratory to the clinic.

Solid tumors, especially pancreatic ductal adenocarcinomas (PDACs), activate quiescent fibroblasts into cancer-associated fibroblasts (CAFs) that generate dense desmoplastic stroma. This barrier restricts drug penetration and immune infiltration, promoting tumor progression. Here, we engineer Midkine (MDK)-targeting nanobody-functionalized extracellular vesicles (D4-EV) as a precision photoimmunotherapy platform. These vesicles selectively accumulate in the tumor microenvironment through MDK overexpression. Loaded with chlorin e6 (Ce6), Ce6@D4-EV induces immunogenic cell death upon light irradiation, triggering dsDNA release and cGAS-STING activation in tumor-associated macrophages. Concurrently, it reprograms CAFs, reduces extracellular matrix deposition, improves vascular perfusion, and alleviates hypoxia. This stromal-immune remodeling substantially enhances the therapeutic efficacy of immune checkpoint blockade, adoptive T cell therapy, and chemotherapy, leading to prolonged survival in multiple MDK-positive preclinical tumor models. The platform provides a promising strategy to overcome stromal barriers in desmoplastic tumors.

Introduction: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis, driven by metabolic reprogramming and immune evasion. The role of T-complex protein 1 subunit beta (CCT2) in HCC remains unclear. This study aimed to elucidate the function of CCT2 in HCC tumorigenesis. Methods: Bioinformatics analysis and Clinical samples investigation were integrated with in vitro and in vivo experiments to investigate CCT2's role in HCC metabolism and immune modulation. The glycolytic activity was assessed by measuring extracellular acidification rate, glucose uptake, lactate levels, and metabolomic profiles. Coimmunoprecipitation or GST pulldown assays confirmed CCT2 interactions with aldolase A (ALDOA) and glutathione S-transferase P (GSTP1), while THP1 co-culture assays evaluated tumor immune crosstalk. Results: CCT2 directly interacts with and stabilizes the glycolytic enzyme ALDOA, as shown by co-immunoprecipitation and metabolic assays revealing increased extracellular acidification rate, glucose uptake, and lactate production in HCC cells. Genetic depletion of CCT2 suppresses tumor cell proliferation and migration in vitro and inhibits tumor growth in vivo. Furthermore, co-culture and exosome treatment experiments reveal that CCT2 promotes M2 macrophage polarization and establishes an immunosuppressive tumor microenvironment through coordinated metabolic and exosome-mediated mechanisms. In mouse models, CCT2 knockdown significantly enhances the antitumor efficacy of PD-1 blockade. Conclusions: CCT2 stabilizes ALDOA and facilitates exosome-mediated immunosuppressive signaling, thereby linking metabolic reprogramming to immune evasion in HCC and supporting its potential as a mechanistically informed therapeutic target.

BackgroundMicrovascular invasion (MVI) is closely related to the recurrence and metastasis of hepatocellular carcinoma (HCC), but the underlying cellular mechanism remains largely elusive. This study aims to elucidate the regional cellular discrepancy between MVI-positive (MVI+) and MVI-negative (MVI-) HCC by integrating Spatial transcriptomics (ST) and spatial metabolomics (SM).Methods and findingsST and SM were performed on six tissue samples from four patients (including 2 MVI+, 2 MVI-, and 2 paratumor tissues), with the integration of 79 public single-cell RNA sequencing datasets of HCC. Patient identity was used as a covariate in the linear equation for regional differentially expressed gene analysis with the ST data. Clinical validation was conducted through multiplex immunofluorescence staining in 79 patients, together with external validation in the cancer genome atlas (TCGA)-liver hepatocellular carcinoma (LIHC) cohort (n = 299) and an independent microarray dataset (n = 62). For cell-type-specific metabolic profiling, spatial transcriptomic-metabolic registration was performed. The functional roles of key metabolites were further validated in vitro using inflammatory cancer-associated fibroblasts (iCAFs) derived from hepatic stellate cells (HSCs) and primary CAFs through co-culture models and various functional assays assessing cell proliferation, migration, and invasion. In the tumor lesion, a malignant STMN1+HMGN2+GPC3+ cell subtype enriched in MVI+ HCC was identified, which exhibited enhanced proliferative activity and was associated with poor prognosis. This finding was further confirmed in a local cohort of 79 patients, where multiplex immunofluorescence staining for the three genes (STMN1, HMGN2, and GPC3) showed significantly higher expression in the MVI+ group than in the MVI- group (p = 0.046). Integrated SM analysis further revealed that this cell population underwent metabolic reprogramming characterized by suppressed glycerolipid metabolism. In the tumor capsule, iCAFs-related genes were downregulated in MVI+ cases, and iCAFs were located distally from the tumor boundary. Spatial metabolite mapping showed a strong correlation between taurine and iCAFs, and functional assays demonstrated that taurine promotes HCC proliferation and migration by suppressing iCAF activity. One limitation of this study is the small sample size of spatial omics data, which hinders a more complete molecular functional analysis of the STMN1+HMGN2+GPC3+ cell subtype and iCAFs in MVI+ HCC. Larger-scale ST cohorts are required to further validate and expand the findings of this study.ConclusionsThis integrative spatial atlas proposes a hypothesis that there exists a highly proliferative and metabolically reprogrammed malignant cell subtype in the tumor lesion of MVI+ HCC, and that taurine in the tumor capsule modulates iCAF activity to influence tumor progression. The exploratory results provide mechanistic insights into MVI-related HCC progression and offer potential avenues for targeted therapeutic intervention of MVI+ HCC.

The continuously rising incidence and persistently high mortality of hepatocellular carcinoma (HCC) have created an urgent need for a deeper understanding of the molecular mechanisms underlying this disease. In the present study, leveraging multiple HCC transcriptome databases, we employed expression analysis, correlation analysis, Gene Set Variation Analysis (GSVA), and cox regression analysis to identify that aberrant upregulation of PDIA6 represents a promising prognostic biomarker associated with adverse clinical outcomes in HCC. Using a series of in vitro oncology research approaches, as well as nude mouse models of subcutaneous tumor formation and lung metastasis, we experimentally validated that PDIA6 promotes the proliferation and metastasis of HCC cells. Through transcriptome sequencing analysis and subsequent rescue experiments, we further confirmed that PDIA6 enhances HCC cell proliferation and migration by activating the Wnt signaling pathway. Combined analysis via immunoprecipitation-mass spectrometry and proteomics revealed that PDIA6 significantly downregulates the expression of the tumor suppressor gene AKAP12. Subsequent rescue experiments demonstrated that PDIA6 drives HCC progression in a manner dependent on the reduced expression of AKAP12. Utilizing protein half-life assays, ubiquitination assays, and co-IP experiments, we uncovered the underlying mechanism: PDIA6 competitively binds to the UCH domain of USP24, which impairs the deubiquitinating activity of USP24 towards AKAP12. This ultimately leads to enhanced K48-linked ubiquitination of AKAP12 and its subsequent proteasomal degradation. We further verified, using specific activators, that AKAP12 inhibits the Wnt signaling pathway in a PKA-dependent manner. In vivo, targeted inhibition of PDIA6 exhibited a more potent therapeutic effect on Wnt-positive HCC tumors.Conclusion Collectively, our study demonstrates the HCC-promoting mechanism of the PDIA6-AKAP12-Wnt signaling axis and highlights its great potential for the development of therapeutic targets in HCC.

Background & Aims: The transition to liver fibrosis represents a crucial and irreversible transition in chronic liver diseases, with liver fibrosis being a key driver of the progression to life-threatening complications, including cirrhosis and hepatocellular carcinoma (HCC). However, effective pharmacological therapies for liver fibrosis are lacking. Our study investigated the role of chimeric antigen receptor (CAR)-T cells in targeting and eliminating activated hepatic stellate cells (HSCs) for the treatment of liver fibrosis. Methods: We engineered CAR-T cells targeting fibroblast activation protein (FAP), a cell surface protein specifically overexpressed on activated HSCs, and evaluated their therapeutic effects on liver fibrosis across four different mouse models. Results: FAP CAR-T therapy significantly alleviated liver fibrosis across multiple etiologies (p <0.0001, n = 10). Mechanistically, the treatment specifically eliminated activated HSCs (p <0.0001, n = 10) and markedly increased hepatic T cell infiltration (p <0.001, n = 10). The antifibrotic efficacy of FAP CAR-T cells exceeded that of a FAP inhibitor (p <0.001, n = 6). Furthermore, the therapy effectively prevented the progression of HCC (p <0.01, n = 20). Conclusion: Overall, our study shows that cell therapy targeting activated HSCs can ameliorate liver fibrosis and HCC, providing a novel therapeutic approach for these conditions. Impact and implications: The global disease burden of liver fibrosis remains significant. Our study provides a novel therapeutic approach, demonstrating that cell therapy targeting activated HSCs can improve liver fibrosis and HCC. These results provide an important theoretical foundation for clinicians and translational researchers. Although further studies are needed to evaluate safety and efficacy before clinical translation, this approach could ultimately offer a cell therapy option to halt disease progression in patients with advanced liver fibrosis.

PABPC1 Ki67 acetylation enhances its binding affinity for GCLC mRNA

Cholangiocarcinoma (CCA) is a rare and highly aggressive malignancy originating in the bile ducts. Owing to limitations involving pathological sampling, the clinical differentiation of CCA from benign biliary diseases remains challenging. This study aimed to evaluate the differences between the bile lipidomes of CCA patients and those of patients with benign disease to develop a bile lipid classifier that can help to differentiate CCA from benign conditions. Bile samples were collected by endoscopic retrograde cholangiography (ERCP) from patients with CCA or benign disease. The participants were divided into three cohorts: the first two cohorts underwent untargeted lipidomic analysis, whereas the third cohort was subjected to targeted lipid quantification. Untargeted lipidomic analysis was performed via ultrahigh-performance liquid chromatography coupled with ion mobility quadrupole time-of-flight mass spectrometry (UHPLC/IM-QTOF-MS). Targeted lipid quantification was conducted via UHPLC‒MS/MS in multiple reaction monitoring (MRM) mode. Lipid features were screened to construct a bile lipid classifier using the machine learning algorithm, least absolute shrinkage and selection operator (LASSO) regression, followed by cross-validation in two cohorts. The selected lipid features were further validated by targeted quantification in the third cohort. The functions of the significantly differentially abundant lipids in proliferation were validated in CCA cell lines. In total, 241 bile samples were collected and divided into three cohorts for independent lipidomic analysis: Cohort 1 included 32 CCA samples and 68 benign controls; Cohort 2 included 30 CCA samples and 30 benign controls; and Cohort 3 included 32 CCA samples and 49 benign controls. There were significant differences in the lipid profiles of the bile samples obtained from patients with CCA and individuals with benign disease, with multiple lipid classes, particularly lysophosphatidylcholine (LPC), significantly downregulated in the CCA group. Multimodule correlation networks constructed via weighted lipid coexpression network analysis (WLCNA) revealed significant associations between lipid modules and clinical traits. A machine learning-based bile lipid classifier, termed BileLipid, was developed for CCA diagnosis; this classifier incorporates six lipid features. This classifier achieved areas under the receiver operating characteristic curve (AUCs) of 0.943, 0.956, and 0.828 in Cohorts 1, 2, and 3, respectively. Additionally, the significantly downregulated lipid LPC in CCA bile was found to significantly inhibit the proliferation of CCA cell lines, suggesting its potential role as a protective factor in CCA. This study not only identified lipidomic alterations in CCA using bile samples but also established and validated a bile lipid classifier with high specificity and sensitivity for distinguishing between CCA and benign bile duct diseases. Our findings highlight the potential of bile lipid biomarkers for improving the differential diagnosis and risk assessment of CCA and preventing potential overintervention in patients with benign biliary disease.