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Accurate delineation of pancreatic tumors on Magnetic Resonance Imaging (MRI) is important for diagnosis, radiotherapy treatment planning, and outcome assessment, but remains challenging due to complex anatomy and subtle tumor appearance. In routine practice, tumor contours on MRI are produced manually, which is time-consuming and subject to inter-observer variability. Radiotherapy on MRI-Linear Accelerator (MRI-Linac) systems further requires fast and consistent Gross Tumor Volume (GTV) contours for online adaptation, yet most public pancreas tumor segmentation benchmarks focus on Computed Tomography (CT). The Pancreatic Tumor Segmentation in Therapeutic and Diagnostic MRI (PANTHER) challenge addresses this gap by benchmarking automatic pancreatic tumor segmentation on MRI. The dataset includes contrast-enhanced T1-weighted diagnostic MRI and T2-weighted MRI-Linac scans with expert pancreas and tumor annotations, organized into two tasks: (1) tumor segmentation on diagnostic MRI and (2) tumor segmentation on MRI-Linac images. Performance was evaluated using overlap metrics, distance-based metrics, and tumor volume error. The challenge attracted 285 registered participants, with 12 and 9 final submissions for Tasks 1 and 2, respectively. On diagnostic MRI, top methods achieved performance close to inter-reader agreement. Multi-reader analysis suggested that models often reproduced the contouring style of the training annotator, highlighting the importance of annotation quality and consensus. In contrast, performance on MRI-Linac images was lower and more heterogeneous, including cases of complete localization failure. PANTHER provides the first public benchmark for pancreatic tumor segmentation on MRI, showing that clinically useful automation is feasible on diagnostic MRI, while robust MRI-Linac GTV segmentation remains an open challenge.

Endoscopic retrograde cholangiopancreatography-guided transpapillary biliary drainage (ERCP-BD) is the standard for primary palliation of malignant distal biliary obstruction (MDBO), but endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) has demonstrated improved technical success, efficiency, and safety in randomized trials. However, cost-effectiveness data are lacking. In this modeling study, we analyzed the cost-effectiveness of EUS-CDS with lumen-apposing metal stent (LAMS) and ERCP-BD with self-expandable metal stent (SEMS) for primary MDBO palliation. A state-transition Markov model compared EUS-CDS and ERCP-BD over a 1-year time horizon from a US healthcare perspective. The base case was a 70-year-old with locally advanced, unresectable pancreatic cancer, common bile duct dilation >15 mm, and MDBO. Probabilities were derived from meta-analyses of randomized trials. Outcomes were incremental cost-effectiveness ratios (ICERs), with a willingness-to-pay (WTP) threshold of $100 000/quality-adjusted life year (QALY). Extensive sensitivity analyses were performed. EUS-CDS with LAMS was cost effective versus ERCP-BD with SEMS for primary treatment of MDBO at an ICER of $47 711/QALY. In one-way sensitivity analyses, EUS-CDS remained cost effective if it cost <$15 502 or if ERCP-BD cost >$11 174. ERCP-BD would become cost effective if technical success was >91%, reintervention <11%, or postprocedural pancreatitis <4%. Probabilistic sensitivity analysis showed EUS-CDS remained cost effective in 74.1% of iterations at a $100 000/QALY WTP threshold. In patients with MDBO and biliary dilation >15 mm, EUS-CDS with LAMS may be not only a clinically preferred option but also an economically viable primary approach. Continued efforts to minimize LAMS costs, decrease stent dysfunction, and identify optimal anatomic indications are warranted to facilitate wider adoption.

Traditional CRISPR-Cas12a mutation detection systems are limited by poor single-base specificity, target-specific crRNA redesign, and insufficient sensitivity for low-abundance mutations, restricting their clinical liquid biopsy applications. Herein, we developed a crRNA-universal, sensitive and specific CRISPR-Cas12a detection platform, termed DESIC (double-end blocker and split-input mediated CRISPR-Cas12a system), for single-base mutation detection. The DESIC system adopts two key structural designs: double-end blocker (DEB) and duplicated split-input (SIN). The DEB spatially isolates crRNA recognition and target-binding regions, enabling universal detection of various mutation sites without crRNA redesign. The SIN strategy amplifies thermodynamic differences from single-base mismatches, greatly improving single-nucleotide discrimination. We targeted four prevalent pancreatic cancer KRAS mutations (G12D, G12R, G12V, Q61H) and optimized the system to achieve optimal discrimination. The optimized DESIC system exhibited ultra-low limits of detection down to 0.01% mutant allele fraction with reliable linear quantitative performance. Clinical validation using 15 pairs of pancreatic cancer tissue and peripheral blood samples confirmed that DESIC results were highly consistent with gold-standard NGS data. With a flexible modular design, this low-cost, easy-operated platform can be readily extended to multiple tumor mutations, holding great potential for tumor liquid biopsy and early molecular diagnosis.

Exogenous L-glutamine has preclinical antitumor activity although formal clinical translation has not been attempted. We conducted a single-arm phase 1 trial to assess the safety and preliminary efficacy of clinical-grade, US Food and Drug Administration-approved L-glutamine therapy with gemcitabine and nab-paclitaxel (GA) in participants with treatment-naive, advanced pancreatic cancer (n = 16). The primary endpoint was to determine the recommended phase 2 dose (RP2D) by adaptive Bayesian design across standard doses of GA and a dose range of 0.1-0.3 g kg-1 twice-daily oral L-glutamine. Secondary endpoints included safety and preliminary efficacy of the study combination. The primary endpoint was met with the RP2D reached at maximum doses of L-glutamine and GA. The grade ≥3 treatment-related adverse event rate was 66.7%, primarily from GA. Addition of L-glutamine to GA induced tumor shrinkage in 94% of subjects with a best overall response rate (ORR) of 44% (12.5% complete response). Median progression-free survival and overall survival (OS) were 8.5 months (95% confidence interval (CI) 6-not reached (NR)) and 22 months (95% CI 11-NR), respectively. L-Glutamine induced distinct metagenomic and metabolomic signatures on exploratory analyses in glutamine-treated subjects as a single agent, while the combination of L-glutamine and GA nearly doubled the ORR and tripled the OS compared to historical GA alone (ClinicalTrials.gov registration: NCT04634539 ).

Pancreatic ductal adenocarcinoma (PDAC) is characterized by high resistance to anticancer therapies, which is caused in part by hypovascularization and dysfunctional vessels that inefficiently deliver chemotherapy. Exercise has been shown to improve tumor vascular function and chemotherapy efficacy in preclinical models. Uncovering the mechanism by which exercise modifies tumor vasculature could help identify potential strategies to improve drug delivery. In this study, we evaluated surgically resected PDAC from patients who exercised during neoadjuvant chemotherapy to demonstrate that exercise remodeled PDAC vasculature and improved tumor vascular function in patients. In mice bearing orthotopic PDAC and treadmill exercise, tumor vascular remodeling was dependent on sphingosine-1-phosphate receptor 1 (S1PR1) signaling in endothelial cells, and S1PR1 was necessary for improved chemotherapy efficacy by exercise. Exercise activated S1PR1 in tumor endothelium, improved tumor vascular function, and increased gemcitabine (Gem) delivery and efficacy. Mice with an endothelial cell-specific S1PR1 deletion did not display exercise-induced improvements in tumor vascular function or Gem efficacy. These findings demonstrate that exercise increases chemotherapy delivery and efficacy by improving vascular function, defining S1PR1 as a necessary mediator of exercise-induced vascular remodeling. Aerobic exercise induces tumor vasculature remodeling via endothelial S1PR1 to enhance drug delivery and suppress pancreatic cancer progression, supporting discovery of exercise efficacy biomarkers and therapeutic strategies for patients unable to exercise.

Ferroptosis, a unique modality of regulated cell death, has become an emerging strategy for tumor therapy. Multiple cellular pathways, including redox homeostasis, iron handling, epigenetic regulation, and metabolic changes, could mediate ferroptosis. Here, we demonstrate that high expression of iron-responsive element binding protein (IRP1)/A + T rich interaction domain protein 3a (ARID3A) inhibits ferroptosis and enhances chemoresistance of pancreatic cancer cells via handling the promoter region of a ferroptosis gene, cytoglobin (CYGB). Mechanistically, the high level of iron leads to nuclear translocation of IRP1 and ARID3A, thereby mediating ARID3A binding to the promoter region of CYGB and down-regulation of chromatin accessibility. The decrease of CYGB expression results in pancreatic cancer cell resistance to ferroptosis, which makes them more resistant to chemotherapy. Clinically, high expression of IRP1 and ARID3A associates with unsatisfactory chemotherapeutic response and poor survival of patients with pancreatic cancer. Our study highlights the role of IRP1/ARID3A complex as a chemotherapy target and its potential in the combined application of ferroptosis drugs.

The highly immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) severely limits the efficacy of current immunotherapies. Identifying key molecular drivers of this immunosuppressive niche is therefore essential for developing new treatment strategies. In this study, through comprehensive bioinformatic analysis of PDAC clinical datasets and systematic experimental validation, we demonstrate that PGK1 is upregulated in PDAC and is associated with poor immune infiltration. Genetic knockdown of PGK1 upregulated STING expression, promoted the recruitment of antitumor immune cells into the tumor microenvironment, and significantly enhanced the in vivo efficacy of STING agonist treatment. Mechanistically, PGK1 stabilizes DNMT1 by blocking its ubiquitination-mediated degradation, which in turn promotes methylation of the STING promoter and suppresses its transcription. Our findings reveal a non-metabolic role of PGK1 in promoting an immunosuppressive microenvironment and propose a promising combination strategy targeting the PGK1-STING axis for the treatment of PDAC.

Targeting the transforming growth factor-β (TGF-β) pathway to reverse the immunologically "cold" tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful, warranting novel therapeutic strategies. We performed multiplex immunohistochemistry on human PDAC samples to correlate cell-type-specific TGF-β pathway activation and CD8+ T-cell abundance and developed a tumor and T-cell coculture to interrogate the TGF-β pathways that promote T-cell-mediated cytotoxicity. We employed newly generated genetically engineered mouse models and a specific pathway inhibitor and confirmed our findings using single-cell RNA sequencing, flow cytometry, and multiplex immunohistochemistry. We performed proteomics and various in vitro and in vivo assays to establish the mechanisms. We found TGF-β-activated kinase 1 (TAK1, Map3k7) to be aberrantly activated in PDAC cells and correlates with T-cell dysfunction. Pharmacological inhibition with Takinib, or genetic deletion of tumor Map3k7 in an autochthonous p48-Cre/Trp53f/f/LSL-KrasG12D genetically engineered mouse model, enhances CD4+ and CD8+ effector T-cell infiltration and renders immune checkpoint blockade effective. Mechanistically, TAK1 inhibition induces DNA damage and cytoplasmic DNA leakage, which activates the cyclic GMP-AMP synthase-Stimulator of Interferon Genes DNA sensing pathway, triggering inflammatory responses that promote adaptive immune cell infiltration. At the molecular level, TAK1 phosphorylates Ephrin Receptor A2 at Serine 897, which in turn phosphorylates RAD51 at Tyrosine 315, a key DNA repair protein involved in homologous recombination. We uncover TAK1 as a critical mediator in maintaining genomic integrity and highlight its potential as a therapeutic target to induce an inflamed tumor microenvironment that sensitizes PDAC to immune checkpoint blockade.

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation; however, how selective autophagy regulates ferroptotic sensitivity remains incompletely understood. Here, we identify RAB8A as a selective autophagic substrate and negative regulator of ferroptosis. Quantitative proteomic analyses reveal that ferroptotic stress induces ATG5- and ATG7-dependent degradation of RAB8A. Mechanistically, ferroptotic stimuli induce RNF126-dependent polyubiquitination of RAB8A and subsequent SQSTM1-mediated autophagic degradation. Functionally, loss of RAB8A sensitizes cancer cells to ferroptosis, whereas expression of the degradation-resistant active mutant RAB8AQ67L suppresses ferroptotic cell death. RAB8A interacts with TFRC and facilitates stress-induced redistribution of TFRC from the plasma membrane toward endolysosomal compartments. RAB8A deficiency impairs TFRC clearance, enhances transferrin-dependent iron uptake, and increases intracellular Fe2+ accumulation and lipid peroxidation. In fibrosarcoma and pancreatic cancer xenograft models, RAB8A depletion enhances the antitumor efficacy of ferroptosis-inducing therapy. Clinically, RAB8A is upregulated and associated with poor prognosis and ferroptosis resistance in pancreatic cancer. Collectively, these findings establish an autophagy-RAB8A-TFRC axis that regulates ferroptotic sensitivity.

Clinical-grade RAS inhibitors raise an unresolved question as to whether KRAS alleles impose constraints on adaptive resistance that can be exploited therapeutically. Using daraxonrasib (RMC-6236), a multi-selective RAS(ON) inhibitor, we compared resistance mechanisms between KRASG12D and KRASG12R, mutants with fundamentally different RAS network dynamics. Daraxonrasib inhibited KRASMUT primarily through steric occlusion of effector binding, while engaging RASWT only modestly (~20%). KRASG12R was marked by its inability to transactivate RASWT, and daraxonrasib resistant KRASG12R PDAC cells utilized EGFR/RASWT-GTP signaling as the dominant adaptive route. In contrast, KRASG12D resistance arose through retained KRASG12D-GTP signaling, with a decrease of cyclophilin A (CypA) protein, the binding partner required for daraxonrasib activity. The shift from KRASG12R dependence to EGFR/RASWT dependence conferred sensitivity to trametinib. As clinical confirmation, a KRASG12R PDAC patient who progressed after 10 months on daraxonrasib showed intratumoral EGFR/RASWT activation, and rapid 3D-bioprinted patient-derived tumoroid modeling predicted sensitivity to trametinib-based combination therapy. Despite the aggressive disease trajectory and lack of response to the two immediately preceding lines of therapy, sixth-line trametinib-based combination therapy achieved approximately 5 months of disease control, and this patient ultimately achieved 40 months of overall survival, far exceeding the 8-12 month median for metastatic PDAC. Collectively, these data establish a framework in which allele-specific RAS network topology dictates the adaptive resistance landscape, enabling rational selection of targeted therapies with meaningful clinical benefit in metastatic PDAC.

The liver possesses an extraordinary capacity to regenerate after injury or surgical resection, a process highly dependent on the coordinated orchestration of the immune microenvironment. Although macrophages are recognized as pivotal coordinators of hepatic tissue repair, the precise checkpoints governing their functional transitions during regeneration remain elusive. Here, we identify the glutamine transporter SLC1A5 (Solute Carrier Family 1 Member 5) as a critical metabolic gatekeeper of macrophage function during liver regeneration. Using a mouse model of partial hepatectomy, we show that SLC1A5 is markedly upregulated in monocyte-derived macrophages at the peak of regeneration. Myeloid specific deletion of Slc1a5 (Slc1a5fl/flLyz2cre) severely impairs hepatocyte proliferation and diminishes the expression of macrophage derived regenerative factors. Mechanistically, Slc1a5 deficiency depletes intracellular glutamine, which triggers macrophage senescence and drives a pro-inflammatory phenotype. This senescent state selectively downregulates Gas6 (Growth Arrest Specific 6), a crucial bridging ligand for efferocytosis, thereby impairing apoptotic cell clearance and exacerbating local inflammation. Strikingly, exogenous Gas6, senolytic Quercetin therapy, or in vivo L-glutamine supplementation successfully alleviates macrophage senescence, reinstates Gas6 mediated efferocytosis, and rescues defective liver regeneration. Collectively, our findings reveal a novel 'Slc1a5-glutamine-senescence-efferocytosis' axis that dictates macrophage driven tissue repair. This study not only uncovers a fundamental immunometabolic mechanism but also highlights glutamine supplementation and senolytics therapy as promising clinically strategies to accelerate liver regeneration.

Ischemia-reperfusion (I/R) is a common and unavoidable phenomenon during surgeries such as hepatectomy and liver transplantation, severely affecting patient prognosis. However, clinically intervention and treatment measures remain very limited. Using human hepatocyte organoid hypoxia-reoxygenation (H/R) and murine hepatic ischemia-reperfusion (I/R) models, we demonstrate that the microbiota-derived flavonoid desaminotyrosine (DAT) attenuates I/R-induced hepatic injury by suppressing inflammation and apoptosis while promoting the abundance of probiotic Bifidobacterium in the gut. Through integrated spatial transcriptomics and metabolomics, we identified that DAT specifically alters the MAPK signaling pathway/ ferroptosis gene transcriptome in the portal vein (PV) zones, promotes the production of antioxidants (taurine) in the central vein (CV) zones, reduces the level of pro-ferritinosis substrates (arachidonic acid), thereby enhancing the expression of GPX4 and Nrf2, inhibiting ferroptosis, then ameliorate hepatic I/R injury. Meanwhile, the pseudo-germ-free mouse model confirmed that DAT alleviated hepatic I/R injury in a gut microbiota dependent manner. DAT reduces hepatic I/R injury by increasing the abundance of gut Bifidobacterium pseudolongum (Bif). Our research results reveal a novel microbial metabolite that improves hepatic I/R injury, clarify the inhibitory effect of DAT on ferroptosis, discover new therapeutic uses of DAT, and identify Bif as a potential novel probiotic for preventing liver I/R injury, providing new options for the preventive treatment of liver I/R injury.

Hepatoblastoma (HB) is the most common primary liver malignancy in childhood, yet its molecular determinants, functional dependencies, and therapeutic vulnerabilities remain incompletely characterized. Integrative analyses combining transcriptomic profiling with functional genomic datasets provide a strategy to identify essential genes, biomarkers predictive of tumor behavior and treatment response. Differential expression analysis comparing HB tumors with normal liver was processed on training cohort. These genes were integrated with DepMap CRISPR-Cas9 dependency scores to prioritize HB-essential candidates. Elastic Net regression was used to derive a 16-gene predictive signature, which was validated in an external cohort. Single-cell RNA-seq datasets were analyzed to assess expression patterns across hepatic and tumor-associated cell populations. A supervised deep-learning classifier was trained on single-cell profiles to distinguish tumor cells from hepatocytes, and SHAP values were computed to interpret gene contributions. Drug-gene interactions were queried using curated repressive compounds from DGIdb, and approved drugs were screened for relevance in pediatric cancer clinical trials. A total of 789 genes were found overexpressed in HB tumors from the training transcriptome cohort. Chronos DepMap analysis identified 73 HB-essential genes that were not essential in adult liver cancer cell lines (hepatocellular carcinoma and cholangiocarcinoma). Elastic-net tuning based on the expression of 16 HB-essential genes in the split training cohort enabled robust tumor-normal discrimination, with AUC = 0.88, specificity = 0.90, and sensitivity = 0.90 in internal validation. This performance was confirmed in an independent external cohort, achieving AUC = 0.99, specificity = 1.00, and sensitivity = 0.98. Single-cell validation further demonstrated tumor-specific enrichment of the signature. The deep-learning classifier (tumor cells vs. normal hepatocytes) reached high accuracy (AUC = 0.99; F1-score = 0.97), with SHAP analysis highlighting PEG10, GREB1, PLCB4, RHOBTB1, CRIM1, FSD1L, CORO2A, KIT, ANKRD50, HDAC11, ZNF233, SEMA7A, and FABP4 as major contributors. Six of these genes were confirmed to be absent or lowly expressed in the background liver microenvironment. Drug-gene interaction analysis identified HDAC11 as a potential therapeutic target of approved drugs used in pediatric oncology. This integrative framework combining transcriptomics, CRISPR dependency mapping, machine learning, and pharmacogenomic annotation identifies clinically relevant HB-essential genes and predictive molecular signatures for tumor identity. The derived expression-based scores provide tools for patient stratification, while drug-gene mapping highlights actionable vulnerabilities on HDAC11 with pediatric approved drugs that support rational drug repurposing strategies in hepatoblastoma.

Relacorilant (LIFYORLI™) is a non-steroidal, selective glucocorticoid receptor II (GR II) antagonist being developed by Corcept Therapeutics for the treatment of various solid tumours (including ovarian cancer, fallopian tube cancer, peritoneal cancer, pancreatic cancer and prostate cancer) and Cushing syndrome. Relacorilant received its first approval in the USA on 25 March 2026 for use in combination with nab-paclitaxel for the treatment of adults with platinum-resistant epithelial ovarian, fallopian tube or primary peritoneal cancer who have received 1-3 prior systemic treatment regimens, at least one of which included bevacizumab. This article summarizes the milestones in the development of relacorilant leading to this first approval for platinum-resistant ovarian, fallopian tube or peritoneal cancer.

Metabolic reprogramming within the tumor microenvironment (TME) impairs antitumor immunity and compromises the efficacy of immunotherapy. Through multiomics-based metabolic subtyping in intrahepatic cholangiocarcinoma, we identified a subgroup with the worst prognosis that demonstrates significant enrichment in both cyclooxygenase/arachidonic acid (COX/AA) metabolism and KRAS mutations. Mechanistically, KRAS mutation-mediated NF-κB pathway activation upregulates CXCL5 expression, thereby recruiting CXCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the TME. Concurrently, KRAS mutation drives prostaglandin E2 (PGE2) production in tumor cells, and PGE2, in turn, enhances AA uptake and COX-2 expression in PMN-MDSCs, establishing an amplifying loop between tumor cells and PMN-MDSCs that exacerbates PGE2 production. PGE2 accumulation potently suppresses the antitumor activity of CD8+ T cells via the prostaglandin E receptor 4 (EP4). Therapeutic targeting of the COX-2-PGE2-EP4 axis, combined with anti-PD-1 immunotherapy, demonstrates profound synergistic efficacy in both KRAS-mutant murine models and patient-derived tumor fragments harboring KRAS mutations. This work identifies a PGE2-COX-2 positive feedback loop between tumor cells and PMN-MDSCs that may serve as a therapeutic vulnerability for KRAS-mutant cholangiocarcinoma.