2508 Background: Advanced hepatocellular carcinoma (HCC) remains a high unmet-medical-need malignancy with limited therapeutic options. Ori-C101 is a novel, armored, autologous GPC3-directed CAR-T cell therapy. Following promising results from early-phase trials (ChiCTR190028121; NCT05652920, BEACON study), we shall herein update outcomes from the BEACON study with focusing on long-term safety, durability of response, and survival after more than 2 years of follow-up. Methods: This is an open-label, multi-center, phase Ib dose-escalation and expansion study enrolled patients (pts) with GPC3 + advanced HCC who had progressed on ≥2 prior lines of systemic therapy (including ICIs and TKIs). A single dose of Ori-C101 was administered via hepatic arterial infusion to enhance regional cell delivery. Integrated analyses assessed safety, tolerability, PK, and efficacy (per RECIST v1.1)，aiming to determine the RP2D. Results: As of Dec 24, 2025, 19 pts received Ori-C101 infusion across 4 dose levels (DLs). All pts had BCLC stage B/C disease and 31.6% (6/19) had extrahepatic metastases. Pts were previously treated with a median of 3 lines (range 2–8) therapies. Safety: Safety remained manageable; no late-onset nor cumulative toxicities were observed through the extended follow-up period. The most common ≥G3 TEAEs (≥10.0%) were transient hematologic toxicities and hepatic laboratory abnormalities. CRS occurred in 100.0% (19/19) of pts; while ≥G3 CRS observed in 42.1% (8/19). No ICANS occurred. One pt at DL4 experienced a DLT of G4 CRS complicated by secondary DIC. Efficacy: In 18 efficacy-evaluable pts, Ori-C101 demonstrated a robust dose-dependent response. Confirmed ORR was 50.0% (9/18); DCR was 77.8% (14/18). At RP2D (DL3), the confirmed ORR and DCR were 66.7% (6/9) and 88.9% (8/9), respectively. Critically, responses were not only rapid but also remarkably durable. 88.9% (8/9) of responders achieved objective response within 1.1 months; at M3, 83.3% (5/6) of responders at the RP2D remained PR. Notably, 1 pt at DL4 achieved CR with a duration exceeding 20 months. Preliminary overall survival data indicate a substantial long-term survival benefit with a median OS of 14.4 months (range 2.6–22.0). In addition, Dose-Exposure-Responses analysis showed dose-dependent CAR-T cells expansion, pharmacodynamic effects and improved tumor response. Conclusions: Ori-C101 demonstrates a manageable safety profile and compelling, durable anti-tumor activity in GPC3 + advanced HCC. The combination of high ORR and prolonged survival benefit distinguishes Ori-C101 as a potential paradigm-shifting therapy for patients who have failed standard-of-care treatments. A phase II/III study is currently underway to further confirm the efficacy and asses the safety of Ori-C101. Clinical trial information: NCT05652920 .

The immunometabolic basis of therapy-resistant colorectal cancer (CRC) peritoneal carcinomatosis with malignant ascites remains poorly defined. Here, we profile ascites immune cells from 20 patients across treatment-naive, chemo/targeted therapy-refractory, and immune checkpoint blockade (ICB)/adoptive T cell therapy (ACT)-resistant CRC. Single-cell RNA sequencing identifies SPP1+ cavity macrophages as drivers of CD8+ T cell dysfunction. Proteomic profiling of 36 patients confirms SPP1 enrichment in ICB/ACT-resistant peritoneal metastases. Mechanistically, SPP1 sustains an M2-like program via PPARγ activation and lipid uptake. SPP1 deficiency reduces PPARγ ligand precursors, triggering NF-κB-driven macrophage reprogramming and reversing CD8+ T cell suppression. Supplementation with 15 d-PGJ2 and fatty acids restores the M2 phenotype. In vivo, macrophage-specific SPP1 knockout enhances cytotoxic T lymphocyte infiltration and ICB efficacy, while SPP1 neutralization overcomes ICB resistance and augments ACT efficacy. Thus, SPP1+ cavity macrophages are central immunometabolic regulators, and SPP1 inhibition represents a promising strategy to overcome immunotherapy resistance in this lethal disease.

OBJECTIVES:Early identification of severe acute pancreatitis (SAP) within 24 h of admission remains challenging and specific biomarkers reflecting the underlying mechanisms, particularly pancreatic necrosis, are lacking. We have previously identified a crucial role of AXL and MERTK in regulating pancreatic necrosis. Their ligands, Growth Arrest-Specific 6 (GAS6) and Protein S (PROS1) can be detected in serum. Therefore, this study aims to evaluate the value of serum GAS6 and PROS1 levels within 24 h of admission for identifying SAP. METHODS:Serum GAS6 and PROS1 were initially assessed in a retrospective discovery cohort and subsequently validated in a prospective cohort using ELISA. A subset of patients provided serial serum samples over 4 weeks to analyze temporal dynamics and correlations with disease severity. RESULTS:A total of 869 AP patients were enrolled. Serum GAS6 levels were significantly elevated and PROS1 levels reduced compared with healthy controls, with greater changes in moderately severe and severe cases. As a single marker, GAS6 showed robust performance for predicting SAP (AUC = 0.722, 95%CI: 0.620-0.832), outperforming CRP (AUC = 0.595) and BUN (AUC = 0.681), and comparable to SIRS (AUC = 0.659), BISAP (AUC = 0.755), and APACHE-II (AUC = 0.797). The GAS6+BISAP combination yielded an AUC of 0.818, significantly superior to GAS6 alone (p = 0.001), SIRS (p = 0.013), CRP (p = 0.002), and BUN (p = 0.015), and numerically higher than APACHE-II (0.818 vs. 0.797). The temporal dynamic changes of both further correlated with disease severity. CONCLUSIONS:Serum levels of GAS6 measured within 24 h provide a valuable, rapid approach for identifying SAP, and when combined with established scoring systems, can further improve performance.

Helicobacter pylori (H. pylori), one of the main predisposing factors for the development of gastric cancer (GC), is a key factor affecting intracellular ROS and iron metabolism. Ferroptosis is characterized by iron-dependent regulated cell death resulting from excessive lipid peroxidation and is a significant process in this context. Nevertheless, the intricate relationship between H. pylori and ferroptosis remains elusive. In this study, we find a suppressive effect of H. pylori on ferroptosis. Specifically, H. pylori inhibits RSL3/Erastin-induced ferroptosis in GC cells via Vacuolating cytotoxin A (VacA). Mechanistically, VacA binds to p62 and KEAP1, disrupting their interaction and preventing KEAP1 degradation. This stabilization of KEAP1 inhibits NRF2 nuclear translocation and subsequently suppresses HMOX1 transcription, leading to reduced Fe2+ accumulation and inhibition of ferroptosis. Additionally, cisplatin induces ferroptosis in GC cells, and HMOX1 overexpression further enhances its cytotoxic effect. Finally, we identify that Hemin (an HMOX1 inducer) enhances the antitumor effect of cisplatin in both a cell line-derived xenograft gastric cancer model and a H. pylori-induced murine gastric cancer model. These findings unveil a previously unrecognized role of H. pylori in conferring resistance to ferroptosis and identify HMOX1 as a potential therapeutic target for H. pylori-associated GC. Mechanistic dissection of H. pylori VacA– mediated suppression of ferroptosis reveals a KEAP1/NRF2/HMOX1 axis that modulates cisplatin sensitivity in gastric cancer.

Polybrominated diphenyl ethers (PBDEs) are implicated in dyslipidemia, but the molecular basis of individual susceptibility remains elusive. Here we report an analysis based on the China National Human Biomonitoring cohort, where we integrate exposome, genomic, and metabolomic data to identify 3,571 genetic variants that interact with PBDE exposure to influence dyslipidemia risk. Metabolomic analysis highlights glycine and glycerophosphate as key mediators. A polygenic risk score derived from these PBDE-interactive variants significantly enhances dyslipidemia prediction in highly exposed individuals. Among these, rs9869609 emerges as a candidate causal variant, showing the strongest association with hypercholesterolemia risk (β = 1.18, FDR = 0.0078). Further functional validation using single-base CRISPR/Cas9 editing reveals that the rs9869609-G allele downregulates SLC6A20 expression by strengthening BHLHE40 binding, which further impairs glycine transport and promotes cholesterol accumulation, particularly under 2,2',4,4'-Tetrabromodiphenyl ether exposure. Collectively, our study elucidates a gene-environment interaction mechanism through which genetic variants modulate lipid metabolism in response to PBDE exposure.

AIM:To investigate the expression of Ly1 antibody-reactive clone (LYAR) in gastric cancer (GC) tissues and predict potential drugs targeting its sensitivity. METHODS:We assessed the standardized mean difference (SMD) of LYAR mRNA expression across 20 GC datasets (1,804 GC samples, 858 normal tissues) using multi-center high-throughput data, in-house immunohistochemistry, and CCLE cell expression data. Clinical and pathological relevance of LYAR was evaluated using metrics such as receiver operating characteristic curve, sensitivity, specificity, and likelihood ratios. Additionally, upstream transcriptional regulation and enrichment analyses were performed, and drug sensitivity analysis identified potential drugs for high LYAR expression. RESULTS:LYAR expression was significantly upregulated in GC (SMD: 1.20, 95% CI: 0.89-1.51). The area under the curve was 0.89 (95% CI: 0.86-0.92), with sensitivity 0.74 (95% CI: 0.66-0.81) and specificity 0.89 (95% CI: 0.82-0.94). MYC potentially enhances LYAR expression, promoting GC progression. High LYAR expression indicates sensitivity to AZD compounds. CONCLUSION:LYAR overexpression promotes GC progression and tumorigenesis, suggesting its potential as a therapeutic target.

The 2025 Nobel Prize in Physiology or Medicine was awarded to Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their seminal discoveries identifying and characterizing the immune system’s key mediators of peripheral tolerance—regulatory T cells (Tregs). Tregs are now recognized as critical modulators of immune responses within the central nervous system (CNS), and therapeutic strategies centered on Tregs now represent a promising avenue for the treatment of a broad spectrum of neurological disorders. This highlight synthesizes the evolving understanding of the characteristics of brain Tregs, detailing their specialized immunosuppressive functions that maintain CNS homeostasis, their emerging neuroprotective roles across a spectrum of neurological conditions, and how Tregs show therapeutic potential in neuropsychiatric disorders, including neuroinflammatory, neurodegenerative, and neurodevelopmental disorders. We outline three primary approaches to harness Tregs to treat neurological disorders: increasing Treg numbers via adoptive transfer or low-dose IL-2 therapy; enhancing their specificity and function through genetic engineering; and developing combination strategies, such as co-culture with astrocytes or co-transplantation with neurons. Despite challenges in seeking balance between cell specificity and quantity and maintaining Treg function in inflammatory environments, recent advances underscore the significant potential of Treg-targeted therapies to revolutionize treatment for neuroinflammatory, neurodegenerative, and psychiatric diseases.

Deciphering the composition of the tumor microenvironment (TME) is critical for understanding tumorigenesis and to design immunotherapies. In the present study, we mapped genetic effects on cell-type proportions using single-cell and bulk RNA sequencing data, identifying 3,494 immunity quantitative trait loci (immunQTLs) across 23 cancer types from The Cancer Genome Atlas. Functional annotation revealed regulatory potential and we further assigned 1,668 genes that regulate TME composition. We constructed a combined immunQTL map by integrating data from European and Chinese colorectal cancer (CRC) samples. A polygenic risk score that incorporates these immunQTLs and hits on a genome-wide association study outperformed in CRC risk stratification within 447,495 multiethnic individuals. Using large-scale population cohorts, we identified that the immunQTL rs1360948 is associated with CRC risk and prognosis. Mechanistically, the rs1360948-G-allele increases CCL2 expression, recruiting regulatory T cells that can exert immunosuppressive effects on CRC progression. Blocking the CCL2-CCR2 axis enhanced anti-programmed cell death protein 1 ligand therapy. Finally, we have established a database (CancerlmmunityQTL2) to serve the research community and advance our understanding of immunogenomic interactions in cancer pathogenesis.

Metabolic reprogramming is pivotal for modulating antitumor immunity of T cell. Here, we identify a distinct CD8+ T cell state, designated as pentose phosphate pathway (PPP)-enhanced effector T cell (Tpeec), which is induced by NQO1-mediated redox cycling. We demonstrate that lawsone (Law) serves as a specific NQO1 substrate. The Law-NQO1 axis elevates mitochondrial ROS through NADPH consumption, activating the AKT-FOXO1 signaling cascade to drive effector differentiation. Importantly, this redox-dependent process amplifies PPP activity, redistributing glucose flux to not only enhance mitochondrial fitness but also promote ribose-5-phosphate (R5P) accumulation, endowing Tpeecs with superior proliferative capacity and stemness. Consequently, Tpeecs exhibit robust antitumor efficacy, as validated both in vitro and in vivo. Our findings uncover a critical metabolic axis linking redox cycling to PPP-driven stemness in CD8+ T cells, thereby reconciling their effector function with long-term persistence. This discovery positions NQO1-bioactivatable agents as promising therapeutic tools for optimizing T cell immunotherapy.

Abstract The spread of lung cancer to bone is a devastating complication often linked to resistance against immunotherapy, but the reasons for this connection are poorly understood. Here we show that the transcription factor YBX1 acts as a central regulator driving both bone metastasis and the formation of an immunosuppressive environment in non-small cell lung cancer (NSCLC). YBX1 achieves this by activating distinct signaling pathways (IL6 and CCL5, respectively). Mechanistically, YBX1 protein levels are controlled by glycosylation that marks it for autophagic degradation inside cells. Notably, reduced YBX1 glycosylation was observed in highly bone-metastatic NSCLC cells. Importantly, we identified a drug candidate, Icaritin, which boosts this sugar-modification, leading to YBX1 degradation. This dual action inhibits bone metastasis and re-sensitizes tumors to immune attack. Our work reveals YBX1 as a promising single target for combating bone spread and overcoming immunotherapy resistance.

Drug tolerant persister cells (DTPs) refer to a transient drug-tolerance sub-population of cancer cells characteristics of phenotype plasticity and heterogeneity. This adaptive cell state is a critical transitional phase, standing on the crossroad that cancer cells reacquire drug sensitivity or enter into the permanent drug resistance. Emerging evidences indicate the epitranscriptomic regulations, particularly RNA methylations are the important mechanism underline post-transcriptional regulations of genes expression across all RNA species. RNA is integral to gene expression as messenger RNA (mRNA), transfer RNA (tRNA) and ribosomal RNA (rRNA), which play roles in transmitting information from DNA to the synthesis of functional proteins. Methylation modifications on these RNAs are prevalent and represent a well-recognized non-genetic mechanism, exerting multifaceted regulatory effects on nucleic acid metabolism, such as nucleotide precursor availability, RNA processing dynamics, sub-cellular localization, transcript stability and translational fidelity/ efficiency. This review systematically sorts out the relevant references, demonstrating recent advances on the knowledge of the patterns of methylation modifications on mRNA, tRNA and rRNA, and how these modifications drive the generation and development of DTPs, which hallmarks of epithelial-mesenchymal transition, metabolism shift and immune escape. And then clinical strategies are delineated, leveraging pharmacological modulators of RNA-modifying enzymes alongside non-pharmaceutical lifestyle advice, for the development of therapy strategies preventing DTPs-rooted tumor relapse in this anti-tumor armamentarium with cytotoxic reagents, targeted therapies and immunotherapies.

ABSTRACT Pancreatic cancer is one of the most lethal malignancies. Genome‐wide association studies (GWAS) identify multiple susceptibility loci, but most map to noncoding regions, leaving variant‐to‐gene links unresolved. In this study, a genome‐wide regulatory map is constructed using expression quantitative trait loci (eQTL) analysis of 482 pancreatic tissues, and integrated with a GWAS meta‐analysis to prioritize causal variants. A total of 82 significant variants and 15 target genes for pancreatic cancer risk are identified, with enrichment in cancer‐related pathways. The variant rs11102484 is validated in an independent cohort of 569 cases and 2691 controls. The combined analysis of 5699 cases and 8467 controls confirms that the G allele of rs11102484 significantly reduces pancreatic cancer risk (odds ratio = 0.85, 95% confidence interval = 0.80–0.90, P = 4.83 × 10−8). Functional assays demonstrate that the G allele impairs ZNF263 binding at rs11102484, thereby weakening a long‐range silencer‐promoter interaction and increasing ST7L expression. Elevated ST7L dampens AKT/β‐catenin signaling and suppresses pancreatic cancer cell proliferation, consistent with the protective association. Overall, this study implicates functional genes in pancreatic cancer risk and characterizes a regulatory variant that modulates ST7L expression, advancing the interpretation of GWAS findings and understanding of pancreatic cancer biology.

Understanding the complex cellular and spatial organization of glioblastoma (GBM) and its microenvironment is crucial for improving diagnosis and treatment. Here we integrated 121 spatial transcriptomics, single-cell RNA sequencing, single-cell assay for transposase-accessible chromatin using sequencing and patch sequencing profiles from 100 patients to characterize primary GBM tissue. We identified four malignant cellular communities that exhibited consistent patterns of cell-type compositions, gene expression and intercellular interactions across patients. We identified two subpopulations of mesenchymal-like (MES-like) tumor cells: MES-Hyp, colocalized with monocyte-derived brain macrophages in hypoxic regions; and MES-Ast, associated with endothelial cells, pericytes and vascular smooth muscle cells. We also predicted and experimentally verified cell subtypes and ligand-receptor pairs involved in intercellular communications in each cellular community. Furthermore, patch sequencing analysis revealed that synaptic connections with glioma cells were predominantly formed between neurons and oligodendrocyte-progenitor-like tumor cells. Overall, our study provides insights into the spatial organization and intercellular communication in GBM, offering potential therapeutic targets.

Differences in preoperative body composition are associated with the prognosis of patients with a variety of cancers. The aim of this study was to investigate the effect of preoperative body composition on the prognosis of radically resected distal cholangiocarcinoma patients. A total of 110 patients with pathologically diagnosed distal cholangiocarcinoma who underwent radical surgery from January 2017 to September 2022 were retrospectively analysed. Body composition indices, such as the skeletal muscle index (SMI), subcutaneous fat area (SFA), visceral fat area, and skeletal muscle radiodensity, were measured at the level of the third lumbar vertebra using a segmentation tool (TOMOVISION-sliceOmatic), and the correlation of clinicopathologic variables, including body composition indices, with overall survival (OS) and disease-free survival (DFS) was assessed. In addition, based on the presence of sarcopenia (low SMI) and subcutaneous tissue obesity (high SFA), we assigned the patients to three groups and performed a joint-effects group prognostic analysis. Of the 110 patients included, 18 (16.4%) had preoperative sarcopenia, and 58 (52.7%) had subcutaneous tissue obesity. A total of 56 patients (50.9%) died during the follow-up period, with a median survival of 19 months (IQR: 13.00-32.00). Sarcopenia and low SFA were significantly associated with mortality. Multivariate Cox regression showed that preoperative sarcopenia (HR = 3.13, 95% CI = 1.53-6.10, P = 0.002) and low SFA (HR = 1.92, 95% CI = 1.08-3.45, P = 0.026) were independent predictors of poor OS, and preoperative sarcopenia (HR = 3.23, 95% CI = 1.63-6.11, p < 0.001) and low SFA (HR = 2.01, 95% CI = 1.13-3.47, P = 0.018) were also independent predictors of poor DFS. According to the results of the joint-effects analysis, patients in the SN group (sarcopenia nonobese group) were associated with poorer OS and DFS (p < 0.001). Our study revealed that preoperative sarcopenia and a low SFA were independent predictors of worsening OS and DFS in radically resected distal cholangiocarcinoma patients. Regarding fat depots, subcutaneous adipose tissue seems to have more prognostic value than visceral fat.

Background Leptomeningeal metastasis (LM) is a fatal complication of advanced cancer with limited therapeutic options and poor prognosis. Immune checkpoint inhibitors (ICIs) have shown promise in systemic disease, but intrathecal ICIs efficacy and immunological impact in LM remain unclear. Cerebrospinal fluid (CSF) proteomics may provide a unique window into the CNS immune microenvironment and enable response prediction.Methods We enrolled 62 patients with LM who received intrathecal pemetrexed (InPe) with or without ICIs (InPe+programmed cell death protein-1 (PD-1), InPe+PD-1+cytotoxic T-lymphocyte associated protein 4 (CTLA-4), InPe+PD-1+vascular endothelial growth factor (VEGF)). Matched CSF (pretreatment and post-treatment) and pretreatment serum samples were collected for high-content proteomic profiling using the Olink platform. Differential expression, pathway enrichment, and machine learning-based modeling were applied to identify treatment-induced changes and predictive biomarkers.Results Nearly half of the patients achieved clinical response. Post-treatment CSF showed enrichment of cytokine and chemokine signaling pathways, with a marked decrease in EGF. Adding PD-1 inhibitor restored immune cell function and upregulated interferon-γ. Compared with serum, CSF proteomic profiles provided superior predictive performance (area under the curve (AUC) 0.884 vs 0.780). A five-protein CSF signature (ADGRG1, CD28, CCL23, DCN, IL-15) achieved robust prediction (AUC 0.968 in InPe+PD-1 training cohort, 0.917 in InPe+PD-1+CTLA-4 validation cohort, and 1 in InPe+PD-1 subsequent validation cohort). ADGRG1 was significantly higher in non-responders at baseline (p=0.031) and decreased after treatment, and specific enrichment in dura-derived LM-associated macrophages, suggesting a macrophage-derived source and potential role in LM progression.Conclusions This study provides the first high-content proteomic atlas of intrathecal ICI therapy in LM, identifies intrathecal ICI therapy-specific immune remodeling in LM, and establishes a CSF-based predictive model with high accuracy. ADGRG1 represents a promising biomarker of treatment responsiveness and a potential mechanistic link between macrophage biology and LM progression.

Tumor-associated macrophages (TAMs) play crucial roles in tumor progression. However, the mechanisms underlying the posttranscriptional regulation of TAMs remain largely unknown. Here, we demonstrated that Trmt61a, the "writer" enzyme of tRNA N1-methyladenosine (m1A) modification, is highly expressed in proinflammatory macrophages in tumor microenvironment. We generated conditional knockout (KO) mice for Trmt61a and observed that Trmt61a deletion in macrophages significantly promoted tumor growth. Mechanistically, we identified that m1A maintains the translation of STING, enhances STING-TBK1-IFN-β signaling in macrophages and therefore suppresses tumor cell growth. We further generated TRMT61A-overexpressing human iPSC-derived CAR-macrophage and demonstrated that human TRMT61A effectively promoted antitumor CAR-macrophage therapy in vivo. Collectively, our findings reveal a novel regulatory mechanism of tRNA m1A modification in macrophages, highlighting the antitumor therapeutic potential of targeting tRNA m1A modification in macrophages.