Intrahepatic cholangiocarcinoma (iCCA), the second most common subtype of primary liver cancer around the world, is an aggressive neoplasm with high metastastic potential, which leads to a low rate of curative resections and dismal prognosis. In previous studies, Sulfatase 2 (SULF2) has been reported to regulate various important oncogenic signaling pathways and promote iCCA progression. Further research is needed to explore the role of SULF2 in iCCA metastasis. In this study, we verified the overexpression of SULF2 in iCCA tissues and its positive correlation with advanced stage and poor prognosis. Trans-well migration and invasion assay and mouse models explored the impact of SULF2 on iCCA metastasis in vitro and in vivo. We also demonstrated that SULF2 facilitated iCCA metastasis through upregulating CXCR4 transcription mediated by the transcription factor YBX1. Moreover, SULF2 could recruit USP7 to interact with YBX1 and inhibit Lys48-polyubiquitination of YBX1, stabilizing YBX1 and promoting a functional YBX1/CXCR4 axis. Combining SULF2 monoclonal antibody with SU056 had a synergistic effect in suppressing iCCA progression and metastasis of mouse models. In conclusion, SULF2 promotes iCCA progression and metastasis through an intracellular SULF2-YBX1-CXCR4 axis, and SULF2 monoclonal antibody combined with YBX1 inhibitor SU056 may be a potentially promising treatment strategy for iCCA.

OBJECTIVE:To evaluate the conversion to resection rate (CTRR), treatment safety and short-term oncological outcomes of FOLFOX-hepatic arterial infusion chemotherapy (FOLFOX-HAIC) plus intravenous bevacizumab or cetuximab for initially unresectable colorectal liver metastasis (IU-CRLM). METHODS:Data from a consecutive cohort of IU-CRLM patients who underwent conversion treatment using FOLFOX-HAIC with bevacizumab or cetuximab in Tongji Hospital were reviewed. The CTRR, tumor response, safety of drug treatment and surgery, potential predictive factors, and short-term oncological outcomes were got to preliminarily evaluate this conversion regimen. RESULTS:A consecutive cohort of 42 patients were screened, and finally, 19 patients were enrolled in the study. 13 patients successfully underwent liver resection, the CTRR was 68.4%. Patients in no resection group showed more ratio of prior chemotherapy and prior resection of primary tumor, reduced chemotherapy dose, worse tumor differentiation and more lymphvascular invasion than in resection group. Patients in resection group showed better tumor response, including overall response, objective response, largest tumor diameter and levels of tumor biomarkers after treatment, except for disease control rate, than in no resection group. The incidence of grade≥3 adverse event was 21.1% and no pharmacotherapy-related death occurred in HAIC. The median operative time was 265 min and no grade≥2 intraoperative incidents occurred. The incidence of postoperative complications was 23.1%, but serious complication rate was only 7.7% and no death occurred with 90 days after surgery. CONCLUSION:FOLFOX-HAIC was an effective and safe conversion treatment for IUCRLM without extrahepatic metastasis.

Targeted cancer therapies can enhance in vivo efficacy and decrease side effects by changing the distribution and exposure of specific biomolecules in tissues. Nevertheless, there are many cancer target proteins that cannot be targeted by traditional drugs. Some new technologies and drug design strategies have been applied to overcome these “undruggable” targets, among which the most well-known and classic technology is proteolysis-targeting chimeras (PROTACs). In order to design a better PROTAC structure for targeting “undruggable” targets, we elaborated in detail on the design of protein of interest (POI) ligands, E3 ligase ligands and linkers in PROTAC structures, the predicting of PROTAC ternary complex structures, and the advantages and disadvantages of using carriers in PROTAC delivery systems. In addition, this article also reviews the current research status of PROTAC targeting “undruggable” targets, such as kirsten rat sarcoma (KRAS), epidermal growth factor receptor (EGFR), c-Myc and p53. The challenges faced by PROTACs and the possible solutions were discussed, and the possibility of PROTAC broadening the range of drug therapeutic targets, especially the “undruggable” target, was prospected.

Background/Objectives: Post-hepatectomy liver failure is one of the most serious complications after liver resection for hepatocellular carcinoma and is associated with high morbidity and mortality. Traditional clinical scoring systems and statistical models provide limited predictive accuracy. This study aimed to develop and internally validate a deep learning model for predicting post-hepatectomy liver failure using multicenter clinical data. Methods: A retrospective cohort of 498 patients from six centers undergoing curative-intent liver resection for hepatocellular carcinoma was analyzed. Preoperative biochemical parameters, intraoperative surgical variables, and tumor-related characteristics were incorporated into a deep neural network, with logistic regression as a baseline comparator. Data splitting was performed before preprocessing, and imputation/scaling parameters were fitted on the training set only to prevent information leakage. Discrimination was assessed using the area under the receiver operating characteristic curve (AUC) and precision-recall (PR) curves; calibration was assessed using calibration plots and Brier score; and clinical utility was assessed using decision curve analysis (DCA). A sensitivity analysis using a preoperative-only feature set (excluding intraoperative variables) was also conducted. SHapley Additive exPlanations were used to determine variable importance. Results: The deep learning model achieved AUCs of 0.914, 0.892, and 0.906 in the training, validation, and test sets, outperforming logistic regression (0.782, 0.757, and 0.773). Key predictors included ALBI and MELD scores, prothrombin time, intraoperative blood loss, and resection extent. Calibration and decision curve analysis further supported the robustness and clinical utility of the model. Conclusions: The deep learning model provides improved predictive performance for post-hepatectomy liver failure compared with logistic regression in an internally validated multicenter cohort and may support perioperative risk stratification and surgical planning.

Background Cholangiocarcinoma (CCA) is a highly lethal malignant tumour with increasing incidence. Current therapies exhibit limited benefits, which urgently demand the identification of novel therapeutic targets. Objective We aimed to identify potential therapeutic targets for CCA and broaden current therapies. Design Potential therapeutic targets for CCA were identified by sgRNA library screening and validated in preclinical models. Multi-omics sequencing and various experimental approaches were performed to validate the mechanism by which Aurora kinase B (AURKB) regulates CCA progression and the immune microenvironment, supported by clinical samples from public data sets and Tongji Hospital cohorts. The translational therapy was comprehensively validated in CCA organoid, patient-derived xenograft and preclinical murine models. Results AURKB was identified as a highly expressed and targetable kinase in CCA. Knockout of AURKB significantly inhibited CCA progression, reduced CD8 + T cell exhaustion and enhanced antitumour response. Mechanistically, AURKB promoted the generation of histone H3 lysine 9 tri-methylation (H3K9me3)/serine 10 phosphorylation, leading to a decrease in the enrichment of H3K9me3 at the neutral cholesterol ester hydrolase 1 (NCEH1) promoter, thereby increasing NCEH1 expression and cholesterol levels in tumours. High AURKB expression in clinical samples predicted poorer outcomes in patients with CCA undergoing neoadjuvant chemoimmunotherapy and was associated with cholesterol accumulation within tumours. AURKB inhibitor or simvastatin can suppress CCA progression and significantly enhance sensitivity to chemoimmunotherapy. Conclusions AURKB regulates cholesterol levels and immune microenvironment in tumours, highlighting that targeting AURKB or adopting cholesterol-reducing strategy holds promise for CCA treatment, especially in conjunction with first-line chemoimmunotherapy.

Evidence directly comparing robotic and open hepatectomy for IWATE expert-level liver resection remains limited. This study aimed to compare perioperative outcomes between the two approaches in a high-volume hepatobiliary center. We reviewed 1706 consecutive patients who underwent hepatectomy for intrahepatic lesions between January 2024 and December 2025. Among them, 232 patients met the criteria for IWATE expert-level resection, including 70 robotic and 162 open cases. The primary outcome was major complications, defined as Clavien–Dindo grade ≥III. One-to-one propensity score matching was used as the primary risk-adjustment method. Overlap weighting was performed as a sensitivity analysis, with an additional malignancy-restricted analysis. Exploratory subgroup analyses were conducted for major complications and textbook outcome in liver surgery (TOLS). Propensity score matching yielded 68 well-balanced pairs. In the matched cohort, robotic hepatectomy had longer operative time than open hepatectomy (median, 240.0 vs 205.5 min; P = 0.002), but lower estimated blood loss (100.0 vs 200.0 mL; P = 0.038) and shorter postoperative length of stay (6.0 vs 9.0 days; P < 0.001). Major complications were comparable between the robotic and open groups (13.2

Nanoparticle mechanical properties, as critical factors in tumor targeting drug delivery, have recently been revealed to regulate cellular biological functions. While macroscopic mechanical stimuli are demonstrated to reprogram tumor-associated macrophages (TAMs), it is unclear how TAMs respond to microscopic stimuli from nanoparticles. Herein, we demonstrated that the stiff 15

Protein kinases contribute to hepatocellular carcinoma (HCC) development and immune evasion, posing major challenges for HCC management. Here we show STE20/SPS1-related proline/alanine-rich kinase (SPAK) as a candidate immune exhaustion–associated gene identified through a pooled screen of protein kinases. By integrating bioinformatic analyses, data from patient cohorts, and functional studies in mouse models and cell lines, we demonstrate that elevated expression of SPAK promotes HCC progression, enhances stemness, drives immune exhaustion, and contributes to resistance to targeted therapies. Mechanistically, SPAK phosphorylates GSK3β at Ser9, thereby inhibiting proteasome-mediated degradation of c-Jun and PD-L1. Additionally, we find that DNMT3B-dependent intragenic methylation of SPAK contributes to its high expression in HCC. Notably, the SPAK inhibitor exhibits potent inhibitory effects and synergizes with PD-1 blockade to enhance antitumor efficacy. In summary, these findings establish SPAK as a driver of oncogenesis and immune exhaustion in HCC and highlight dual inhibition as a potential therapeutic strategy. Protein kinases contribute to hepatocellular carcinoma progression and immune evasion. This study identifies SPAK as a key driver of oncogenesis and immune exhaustion, showing that SPAK inhibition synergizes with anti-PD-1 therapy to enhance antitumor efficacy.

4148 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have demonstrated efficacy in aHCC. Despite improved outcomes with PD-1/PD-L1 inhibitor-based regimens, prognosis remains poor and there is a continued unmet need for alternative therapies with long-term survival benefits. This study aimed to evaluate the effectiveness and safety of IBI310 (anti-CTLA-4 antibody) combined with sintilimab (anti-PD-1 antibody) in the first-line treatment of aHCC. Methods: Pts were randomized in a 2:1 ratio to IBI310+sintilimab group or sorafenib group. The experimental group received IBI310 3mg/kg intravenously (IV) and sintilimab 200 mg IV on day 1 of every 3 weeks. The control group received sorafenib 400 mg orally twice daily (BID) continuously until disease progression, intolerable toxicity, death or other protocol-specified discontinuation criteria. During the study, the IBI310 dose was adjusted to 1 mg/kg every 6 weeks. Primary end points included overall survival (OS) and objective response rate (ORR)assessed by the independent radiology review committee (IRRC) per RECIST v1.1. Secondary endpoint included progression-free survival (PFS), disease control rate (DCR), safety, etc. Results: As of August 2022, 344 patients were enrolled and allocated to Group 1 (G1, IBI310 3mg/kg + sintilimab, n=84), Group 2 (G2, modified-dose IBI310 1mg/kg + sintilimab, n=145) and Group 3 (G3, sorafenib, n=115). Overall, PFS and ORR improved with IBI310+sintilimab vs Sorafenib. The median OS in the primary endpoint was 44.0 months(G1), 36.1 months(G2) and 22.9 months(G3), respectively. Confirmed ORRs were significantly higher in the combination therapy groups (G1: 41.7%; G2: 22.1%) versus the control group (2.6%). Median PFS of three groups were 13.5 months(G1), 6.1 months(G2) and 2.8 months(G3), respectively. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 60.7% (G1), 34.7% (G2), and 35.1% (G3) of patients. Conclusions: Compared with sorafenib group, combination treatment of IBI310 + sintilimab as first-line treatment demonstrated survival benefits and a manageable safety profile in aHCC. Clinical trial information: NCT04720716 . Survival data. IBI310(3mg/kg)+Sintilimab(N=84) IBI310(1mg/kg)+Sintilimab(N=145) Sorafenib(N=115) mOS, m 44.0 36.1 22.9 Confirmed ORR, n(%) 35(41.7) 32(22.1) 3(2.6) mPFS, m 13.5 6.1 2.8

Cancer metabolism is characterized by profound reprogramming, yet the mechanisms enabling rapid and precise adaptation remain incompletely understood. This review establishes post-translational modifications (PTMs) as the central processing unit of oncogenic metabolic reprogramming. PTMs execute a conserved three-tiered regulatory logic: they interpret oncogenic and environmental signals, command metabolic flux, and cement malignant phenotypes through epigenetic and feedback mechanisms. We systematically demonstrate how this PTM-driven logic governs key pillars of cancer metabolism—glucose, lipid, amino acid, and nucleotide utilization—and extends its command to critical cell fate execution programs, including mitochondrial dynamics, autophagy, and ferroptosis. Furthermore, we delineate how PTMs act as master regulators of immunometabolic reprogramming within the tumor microenvironment (TME), directly linking tumor metabolism to T cell exhaustion, myeloid cell polarization, and immune evasion. By integrating recent advances on the determinants and crosstalk of PTM networks, we describe how metabolic plasticity and heterogeneity are encoded at the PTM level, with metabolic gradients shaping distinct “PTM geographies” within tumors. Finally, we translate these insights into clinical prospects, highlighting PTM-based biomarkers, PTM-targeted drugs and emerging therapeutic strategies, including targeted protein degradation, PTM-targeted vaccines and dietary interventions. Deciphering this PTM-encoded program reveals a new landscape of therapeutic vulnerabilities, shifting the paradigm toward rationally targeting the fundamental computational logic that sustains tumors.

BACKGROUND:Interferon (IFN)-stimulated gene 15 (ISG15) is a downstream molecule of the IFN pathways central to many cellular processes. ISG15 mainly exerts its function through a post-translational modification process known as ISGylation. OBJECTIVE:In this study, the role of ISG15 in the activation of hepatic stellate cells (HSCs) and liver fibrosis was examined. DESIGN:Liver fibrosis was established by carbon tetrachloride (CCl4), bile duct ligation (BDL) surgery and metabolic dysfunction-associated steatohepatitis (MASH) diet between HSC-specific deletion of ISG15 (ISG15cKO) and wild type mice. Using genetic strategies in vitro, the role of ISG15 in HSCs was established. Immunoprecipitation, luciferase reporter assays and chromatin-immunoprecipitation assays (ChIP) in combination with proteomics sequencing in HSCs were used to study the associated downstream mechanisms. RESULTS:ISG15 was underexpressed in activated HSCs and fibrotic livers, showing an inverse correlation with α-smooth muscle actin in patients with liver fibrosis. ISG15cKO mice developed spontaneous hepatic fibrosis and showed exacerbated CCl4/BDL-induced fibrogenesis. In vitro, ISG15 modulated HSC activation, proliferation and excessive extracellular matrix production. ISG15 deficiency in HSCs promoted transforming growth factorβ2 (TGFβ2) transcription by enhancing phosphorylated cAMP responsive element binding protein 1 (CREB1) activity, thereby inducing CREB1 binding on TGFβ2 promoter regions to activate TGFβ2/SMAD2 signalling. ISGylation directly binds CREB1 on Lys-304 and Lys-305 to inhibit p-CREB1 activity. Overexpression of ISG15 in HSCs or pharmacological inhibition of CREB1 by 666-15 could abolish ISG15 deficiency-induced liver fibrosis in CCl4-treated mice. CONCLUSIONS:ISG15 regulated HSC activation and liver fibrosis in part via the CREB1/TGFβ2/SMAD2 regulatory pathway. Utilisation of ISG15-CREB1 signalling may be a potential therapeutic target for liver fibrosis.

The bidirectional communication between the liver and bone profoundly influences the development and progression of both liver and bone diseases and significantly affects systemic homeostasis. Through the metabolic and immune crosstalk mediated by hepatokines, osteokines, extracellular vesicles, gut microbiota, and neuroendocrine factors, the liver-bone axis not only affects the progression from chronic liver disease to liver cancer but also modulates the balance of bone formation and resorption as well as bone marrow homeostasis. Furthermore, a dysfunctional liver-bone axis can lead to systemic complications characterized by dyslipidemia and hyperglycemia. In this review, we discuss the pathophysiological changes induced by the dysregulated liver-bone axis and elucidate the specific mediating factors and mechanisms involved. We also summarize the current efforts in translating the liver-bone axis into clinical applications, aiming to provide potential therapeutic strategies for liver and bone diseases.

Background: Hepatocellular carcinoma (HCC) patients without microvascular invasion (MVI) face significant postoperative early recurrence (ER) risks, yet prognostic determinants remain understudied. Existing models often rely on linear assumptions. This study aimed to develop and validate an interpretable machine learning model using routine clinical parameters to predict early recurrence (ER) in MVI-negative HCC patients. Methods: We retrospectively analyzed 578 MVI-negative HCC patients undergoing radical resection. Seven machine learning (ML) algorithms were systematically benchmarked using clinical/laboratory/imaging features optimized via recursive feature elimination (RFE) and hyperparameter tuning. Model interpretability was achieved via SHapley Additive exPlanations (SHAP). Results: The CatBoost model demonstrated superior performance (AUC: 0.7957, Accuracy: 0.7290). SHAP analysis identified key predictors: tumor capsule absence, elevated HBV-DNA and CA125 levels, larger tumor diameter, and lower body weight significantly increased ER risk. Individualized SHAP force plots enhanced clinical interpretability. Conclusions: The CatBoost model exhibits robust predictive performance for ER in MVI-negative HCC, offering a clinically interpretable tool for personalized risk stratification and optimization of postoperative management strategies.

Identification of SLKv promote glycolysis in H3B-8800 responded splicing events

Neutrophils, accounting for 50–70% of circulating leukocytes, exhibit remarkable plasticity in tumor biology. Depending on tumor type and microenvironmental cues, they can exert either anti-tumor or pro-tumor effects. During tumor initiation, neutrophils exposed to chronic inflammation secrete cytokines and oncogenic microRNAs that promote genomic instability and malignant transformation. In tumor progression, neutrophils adopt context-dependent phenotypes and execute diverse functions, including polarization into anti-tumor (N1) or pro-tumor (N2) subsets; secretion of inflammatory and angiogenic mediators; formation of neutrophil extracellular traps (NETs); production of reactive oxygen and nitrogen species (e.g., H2O2 and nitric oxide); and modulation of immune cell infiltration and function within the tumor microenvironment. During metastasis, neutrophils facilitate cancer dissemination through three principal mechanisms: (1) promoting epithelial–mesenchymal transition (EMT) via inflammatory signaling, adhesion molecule interactions, and lipid metabolic support; (2) establishing pre-metastatic niches by remodeling distant organ stroma through NETs and matrix metalloproteinases; and (3) reactivating dormant tumor cells in response to chronic inflammation, viral infection, or stress hormones. Collectively, neutrophils function as central regulators across all stages of tumor evolution, influencing cancer growth, immune evasion, and metastatic progression. This review aims to provide a comprehensive synthesis of neutrophil-mediated mechanisms in the tumor microenvironment and highlight emerging strategies for neutrophil-targeted cancer therapy.

The study of the multifaceted interactions between neuroscience and cancer is an emerging field with significant implications for understanding tumor biology and the innovation in therapeutic approaches. Increasing evidence suggests that neurological functions are connected with tumorigenesis. In particular, the peripheral and central nervous systems, synapse, neurotransmitters, and neurotrophins affect tumor progression and metastasis through various regulatory approaches and the tumor immune microenvironment. In this review, we summarized the neurological functions that affect tumorigenesis and metastasis, which are controlled by the central and peripheral nervous systems. We also explored the roles of neurotransmitters and neurotrophins in cancer progression. Moreover, we examined the interplay between the nervous system and the tumor immune microenvironment. We have also identified drugs that target the nervous system for cancer treatment. In this review we present the work supporting that therapeutic agent targeting the nervous system could have significant potential to improve cancer therapy.

The transmembrane and coiled-coil domains 3 (TMCO3) are highly expressed in many tumors. However, the underlying mechanisms governing the way in which TMCO3 affects the progression of hepatocellular carcinoma (HCC) remain unclear. This study screens out the molecule TMCO3 with high N6-methyladenosine (m6A) modification level in tumor samples compared to the adjacent non-cancerous tissues of three pairs of HCC patients through Methylated RNA Immunoprecipitation Sequencing (MeRIP-seq) and RNA sequencing (RNA-seq). Subsequently, the oncogenic effect of TMCO3 in HCC is verified through in vivo and in vitro experiments. AlkB Homolog 5 (ALKBH5), an m6A demethylase of TMCO3 is then screened out. The following experiments demonstrate that TMCO3 can activate AKT directly through the Phosphatidylinositol-3-Kinase (PI3K) pathway, thus promoting the progression of HCC. Meanwhile, the phosphorylation site on TMCO3: the 85th amino acid-serine, and mutation of this site can directly impair the activity and membrane translocation of AKT is found. Finally, the carcinogenic effect of TMCO3 is further elucidated in HCC through the orthotopic treatment model and the hydrodynamic tail vein injection treatment model. The findings can provide a potential target for targeted AKT treatment in patients with HCC and verify a possible prognostic marker in HCC.

U-13C-glucose–Metabolic Flux analysis in MHCC-97H-SLKv and MHCC-97H-Vector cell lines.