The tumour necrosis factor receptor superfamily (TNFRSF) represents a pivotal signalling network that orchestrates immune homeostasis and regulates cell fate decisions. Lymphotoxin β receptor (LTβR, TNFRSF3), a key TNFRSF member, is predominantly expressed on stromal cells and distinct myeloid subsets. Upon binding to its ligands lymphotoxin α1β2 (LTα1β2) and TNFSF14 (LIGHT), LTβR activates multiple signalling cascades, including canonical and non-canonical NF-κB pathways, thereby playing an essential role in tumour immune regulation. LTβR exerts multifaceted functions in lymphoid organogenesis, chronic inflammation, and tumour microenvironment (TME) remodelling. Notably, it promotes the formation of high endothelial venules and tertiary lymphoid structures, facilitating immune cell recruitment and spatial organisation to shape anti-tumour immunity. Recent studies highlight that LTβR agonists show promising therapeutic potential, particularly in combination with immune checkpoint blockade. This review summarises the biological features of LTβR and its dual regulatory roles in the TME, underscoring its potential as a novel target for cancer immunotherapy.

Tissue-resident bacteria have emerged as modulators of host responses to tumor immunotherapy. However, the immunological and metabolic mechanisms by which tissue-resident microbiota influence immune checkpoint blockade in colorectal cancer (CRC) remain incompletely defined. We profiled the microbial composition of colorectal tissues from CRC patients and identified differentially enriched taxa between tumors and adjacent non-tumor tissues(NTs). By focusing on tissue-resident bacteria within the colorectal tumor microenvironment, immunocompetent mouse models were used to evaluate the impact of Limosilactobacillus reuteri (enriched in NTs) on tumor growth, survival, and anti-PD1 efficacy. Single-cell RNA sequencing combined with flow cytometric analysis was applied to characterize the phenotypic features of CD8⁺ T cells following anti-PD1 treatment with or without L.reuteri. Untargeted metabolomics combined with flow cytometry was conducted to investigate the association between tissue-resident L.reuteri and intratumoral lipid metabolic remodeling. L.reuteri administration significantly enhanced the efficacy of anti-PD1 therapy, reduced tumor burden (MC38: 95

4227 Background: Current non-invasive approaches for the diagnosis of pancreatic ductal adenocarcinoma (PDAC) exhibit inherent limitations in accuracy. Consequently, there exists an urgent and unmet need for novel non-invasive biomarkers exhibiting high sensitivity and specificity to enable PDAC diagnosis. Methods: We employed small RNA sequencing to detect microRNA (miRNA) expression in small extracellular vesicles (sEVs) isolated from plasma samples of study participants (n = 208). A diagnostic model was developed (n = 140) and validated (n = 68) to discriminate between patients with PDAC and non-malignant controls (healthy individuals, chronic pancreatitis, intraductal papillary mucinous neoplasms, serous cystadenomas, solid pseudopapillary tumors, pancreatic cysts, and pancreatic abscesses). Results: The small RNA sequencing analysis of plasma sEV miRNA identified 32 differentially expressed sEV miRNAs between non-malignant controls and PDAC patients. The diagnostic model with the best performance was constructed using 17 sEV miRNAs. The diagnostic model achieved an area under curve (AUC) of 0.939, a sensitivity of 93%, and a specificity of 90% in the training cohort and an AUC of 0.951, a sensitivity of 95%, and a specificity of 83% in the test cohort. We identified the distinct characteristics of plasma sEV miRNAs among non-malignant controls compared to PDAC patients. Moreover, nine negative miRNAs and one positive miRNA were found significantly associated with the death risk of PDAC (all p < 0.05). Conclusions: Our findings demonstrates that plasma sEV miRNA exhibits a highly discriminative biomarker for distinguishing non-malignant group from malignant group, making it a promising tool for the diagnosis of PDAC.

Radiotherapy is a mainstay treatment for esophageal squamous cell carcinoma (ESCC), but radioresistance remains a major clinical challenge. Ferroptosis has been implicated in cancer therapy responses, yet how ESCC cells evade ferroptosis to acquire radioresistance is unclear. Here, ESCC cell lines (ECA109 and TE-1) and a subcutaneous xenograft mouse model were employed. GPX4 was modulated by shRNA or RSL3, and methyltransferaselike 3(METTL3) was knocked down by shRNA or inhibited by DAA or STM2457. Glutathione peroxidase 4 (GPX4) was overexpressed using a plasmid. Radiosensitivity was assessed by CCK-8, colony formation, and tumor growth assays, while ferroptosis was evaluated by ROS and Fe²⁺ measurements. m6A modification of GPX4 mRNA was analyzed by MeRIP-qPCR, protein interactions by Co-IP and IF, O-GalNAcylation sites by site-directed mutagenesis and VVL pull-down, and protein stability by CHX chase assays. Irradiation (4 Gy) upregulated GPX4, and GPX4 knockdown or RSL3 significantly enhanced radiosensitivity. Mechanistically, irradiation induced METTL3, which installed m6A modifications on GPX4 mRNA, increasing its stability and expression. METTL3 knockdown reduced GPX4, promoted ferroptosis, and sensitized cells to radiation, effects rescued by GPX4 overexpression. The O-GalNAc transferase Glycosyltransferase 2(GALNT2) interacted with METTL3 and mediated its O-GalNAcylation at S64. GALNT2 overexpression upregulated METTL3 and GPX4, suppressed ferroptosis, and promoted radioresistance, which was reversed by METTL3 knockdown or STM2457. Our study identifies a GALNT2-METTL3-GPX4 axis that promotes radioresistance in ESCC by suppressing ferroptosis. Targeting this axis via METTL3 or GALNT2 inhibition may represent a promising strategy to overcome radioresistance in ESCC.

Kidney organoids are important tools for modeling human development and disease, especially in chronic kidney disease (CKD), which is a global health challenge. Current treatment strategies focus on delaying disease progression by managing underlying causes, and in this regard, kidney organoids offer a platform for mechanism-based therapeutics. Advances in the understanding of human induced pluripotent stem cells (hiPSCs) and sophisticated 3D organ culture methods have enabled researchers to replicate human kidney development and disease mechanisms in vitro, thereby opening new avenues for drug testing. Although the methods for generating renal cell lineages are well established, new protocols for inducing lineages, such as the ureteric bud and collecting ducts, have emerged over the past 5 years. Patient-derived or genetically edited kidney organoids have been used to successfully model various genetic kidney diseases, notably polycystic kidney disease, and to generate kidney tissues that closely mimic the morphology of real organs. However, achieving more complex disease modeling and generating transplantable synthetic kidneys still has notable challenges. The present review discusses the application of hiPSC-derived 3D organoids in CKD research and addresses the limitations of current organ culture methods. The present review also examines the impact of CRISPR/Cas9 technology, and investigates potential future directions.

Non-small cell lung cancer (NSCLC) is characterized by high incidence and mortality, with a low five-year survival rate. Lactate metabolism plays a central role in the metabolic reprogramming of NSCLC. Beyond serving as the end-product of glycolysis, lactate accumulates in the tumor microenvironment (TME), contributing to acidification, and can also enter the tricarboxylic acid cycle to participate in energy metabolism. Moreover, the G protein-coupled receptor 81 (GPR81)/phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling axis induces the expression of immune checkpoint molecules, such as programmed death-ligand 1 and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), thereby suppressing the functions of T lymphocytes and natural killer cells and establishing an immunosuppressive microenvironment. Lactate further promotes epithelial-mesenchymal transition and tumor metastasis, and drives NSCLC chemoresistance and relapse via histone lactylation. Clinical studies indicate that enhanced lactate metabolism is associated with NSCLC progression and chemotherapy resistance, while targeting lactate metabolism in combination with immunotherapy exerts synergistic antitumor effects. Therefore, comprehensive inhibition of lactate metabolism together with enhancement of antitumor immunity may improve the efficacy of precision therapy in NSCLC.

BACKGROUND:Esophageal squamous cell carcinoma (ESCC) is a highly aggressive disease that carries a poor prognosis and limited therapeutic efficacy, particularly in advanced stages. While immune checkpoint inhibitors (ICIs) have improved outcomes in some patients, resistance mechanisms remain poorly understood. Keratin 15 (KRT15) has been implicated in tumor progression and immune regulation, yet its role in ESCC immunotherapy resistance is unclear. METHODS:Transcriptome data from 12 ESCC patients receiving neoadjuvant chemoimmunotherapy (NACI) were analyzed, categorizing them into pathologic complete response (pCR) and non-pCR groups. An independent tissue microarray (TMA) of 102 patients was used to assess KRT15 expression and prognosis. Bioinformatics, immunohistochemistry, and immunofluorescence were employed to validate findings, followed by functional validation. RESULTS:KRT15 was significantly overexpressed in non-pCR patients and ESCC tissues, correlating with poor prognosis. Genetic silencing of KRT15 enhanced tumor sensitivity to immunotherapy, with increased intratumoral CD8+ T cells and NK cells, and reduced CD276 expression. Mechanistically, KRT15 interacted with GSK3β to stabilize β-catenin, promoting CD276 transcription and suppressing NK cell function. Rescue experiments confirmed that CD276 overexpression or GSK3β inhibition reversed these effects. CONCLUSION:KRT15 regulated GSK3β phosphorylation to promote β-catenin stability and CD276 expression, thereby inhibiting NK cell function and contributing to immune resistance in ESCC.

BackgroudImmunosuppressant tacrolimus (TAC) induces glucose metabolism disorder and diabetes mellitus (DM) closely associated with intestinal microbiota dysbiosis and reduced bile acid levels, and this study aimed to explore the ameliorative effect and underlying mechanism of hyodeoxycholic acid (HDCA) on TAC-induced DM in rat models.MethodsWe first verified the critical role of intestinal microbiota and bile acids in the pathogenesis of TAC-induced DM via antibiotic-induced gut microbiota depletion, then orally administered HDCA (100 mg/kg) to TAC-induced diabetic rats to evaluate its protective efficacy, detecting glycolipid metabolism indices, targeted bile acid omics, FXR/TGR5 protein expression, serum and ileal GLP/FGF15 levels, and mRNA levels of key metabolic genes including Cyp7a1, Cyp27a1, Cyp7b1, Cyp8b1, Fgfr4, Creb1 and Ppargc1a.ResultsAntibiotic treatment significantly reduced BSH-active gut microbiota such as Bacteroides and Lactobacillus, disrupting the serum bile acid pool and exacerbating diabetic symptoms by altering the gut microbiota-bile acid axis; while HDCA administration markedly improved glucose tolerance and reshaped bile acid profiles in TAC-induced diabetic rats, specifically lowering serum and fecal 12-OH/Non-12-OH BAs ratio via downregulating hepatic Cyp7a1 and upregulating hepatic Cyp8b1 expression. HDCA also suppressed enteroendocrine cell-derived GLP-1 secretion, decreased serum and ileal FGF15 levels, and reduced the expression of ileal FXR as well as hepatic Creb1 and Ppargc1a.ConclusionsCollectively, HDCA exerts a significant ameliorative effect on TACinduced DM by regulating metabolic enzymes and altering bile acid profiles, with the core mechanism involving inhibited enterohepatic FXR-FGF15 axis, increased GLP-1 secretion and suppressed hepatic gluconeogenesis, all of which play key regulatory roles in this protective process.

Background:Radiation-induced liver disease (RILD) is a serious complication of radiation therapy for upper abdominal tumors, the cellular and molecular basis of which remain mostly unclear. Methods and Materials:Single-cell RNA sequencing (scRNA-seq) analysis of rat liver tissues was conducted to identify the key cytokines regulating RILD. Critical downstream target genes of RILD were determined using a chromatin immunoprecipitation (ChIP) assay. The BRL-3A cell line was selected for in vitro experiments. Results:Pathological damage and immune cell infiltration were most severe at 2 weeks after irradiation (IR). ScRNA-seq analysis revealed that Kupffer cells represented the highest proportion of cells after IR (42.4%) and characteristically expressed Il6. Anti-interleukin (IL)-6 could alleviate liver damage and hepatocyte apoptosis after IR, whereas sgp130Fc could not. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the JAK‒STAT signaling pathway in hepatocytes significantly changed after IR. In hepatocytes, STAT3 was significantly activated after IR. ChIP assays indicated that p-STAT3 bound to the promoter of the Ccng1 gene. Flow cytometry revealed that simple addition of exogenous IL-6 significantly aggravated radiation-induced cell apoptosis and cell cycle arrest in BRL-3A cells, and additional Ccng1 knockdown alleviated this damage. Ccng1 knockdown accelerated γH2AX degradation in BRL-3A cells after IR. In cells cultured in IL-6, Ccng1 knockdown upregulated TP53. Conclusions:Paracrine secretion of IL-6 by Kuppfer cells activates STAT3 in hepatocytes through classical signaling. Activated STAT3 increases Ccng1 transcription. CCNG1 protein may promote TP53 degradation. When TP53 is downregulated, hepatocyte apoptosis increases significantly, resulting in atypical RILD.

Colon cancer remains a therapeutic challenge due to limited efficacy of current treatments. This study investigates the synergistic antitumor effects of cordycepin combined with CTLA-4 inhibitors, focusing on their ability to reshape the gut microbiome. By integrating multi-omics approaches, we elucidate the mechanisms underlying the enhanced efficacy of this triple therapy. Our findings reveal that cordycepin combined with CTLA-4 inhibitors significantly improves antitumor efficacy in the MC38 colon cancer mouse model. This enhancement is mediated by the critical role of the Eubacterium brachy group in modulating the tumor immune microenvironment. Based on these results, we propose a "microbiome-immune" triple therapy strategy involving cordycepin, CTLA-4 inhibitors, and Eubacterium rectale. Non-targeted metabolomics analysis using LC-MS identified specific activation of the histidine metabolism pathway, with elevated levels of the key metabolite Cetirizine N-Oxide potentially contributing to enhanced immune activity. Single-cell transcriptomic analysis demonstrated that the triple therapy significantly increased the responsiveness of tumor antigen-specific CD8+ T cells to CTLA-4 inhibitors, thereby boosting their antitumor activity. Moreover, the triple therapy not only enhanced the antitumor functionality of conventional effector CD4+ T cells but also effectively prevented their exhaustion. Mechanistic studies further revealed that the triple therapy suppresses the activity of the Bcl6 regulatory network, thereby reducing the immunosuppressive function of Tregs and destroying the immunosuppressive interplay between myeloid immune cells and Tregs. These results demonstrate a promising "microbiome-immune" dual-targeting strategy for colon cancer with clinical translational potential.

The regulation of T cell exhaustion within the tumor microenvironment plays a pivotal role in shaping the immune response to cancer and determining the efficacy of immunotherapy. However, the molecular factors governing this process in colon cancer remain poorly understood. This study investigates the expression characteristics and functional significance of the transmembrane protein CD82 in the colon cancer immune microenvironment, with emphasis on its regulatory role in CD8+ T cell exhaustion and clinical outcomes. Publicly available transcriptomic datasets were integrated with multiplex immunohistochemistry on colon cancer tissue microarrays to characterize the cell-type-specific distribution of CD82 and its associations with key markers of T cell dysfunction. CD82 expression was markedly increased in tumor-infiltrating immune and epithelial cells compared with normal tissues, particularly within exhausted CD8+ T cells. Elevated CD82 levels showed strong positive correlations with canonical exhaustion markers such as programmed cell death protein 1 and T cell immunoglobulin and mucin domain-containing protein 3. Multiplex immunohistochemical analysis further revealed that enrichment of CD82-positive epithelial regions and expansion of the CD82+TIM-3+PD-1+CD8+ T cell subset were associated with poor prognosis and were confirmed by multivariate Cox regression as independent risk factors for unfavorable survival. In patients who failed to achieve a complete pathological response following immunotherapy, exhausted CD8+ T cells exhibited significantly higher CD82 expression. Single-cell regulatory network analysis identified BATF and BHLHE40 as potential transcriptional regulators of CD82. Collectively, these findings demonstrate that CD82 promotes CD8+ T cell exhaustion, contributing to tumor progression and immunotherapy resistance in colon cancer. This study provides novel insight into the molecular mechanisms underlying immune dysfunction and offers a potential therapeutic target for reversing immunosuppression and improving immunotherapy efficacy in colon malignancies.

Aim:Given the limited availability of safe and effective treatments for inflammatory bowel disease (IBD), we applied an integrated network pharmacology approach to systematically map the targets and pathways of cordycepin, a bioactive compound from Cordyceps militaris, in experimental colitis. Methods:Cordycepin was administered intraperitoneally during dextran sulfate sodium (DSS) exposure in mice, with efficacy evaluated by the disease activity index (DAI) and histopathological analysis. Network pharmacology analysis (TCMSP, CTD, SEA, BATMAN-TCM, GeneCards, and PharmMapper), molecular docking, and molecular dynamics (MD) simulations were performed to identify and validate potential core targets. AKT1 and tight junction protein ZO-1 expression in colonic tissues was assessed by immunohistochemistry (IHC). The involvement of AKT signaling in cordycepin's effects on tight junction integrity and mitochondrial function was further investigated in lipopolysaccharide (LPS)-treated Caco-2 cells using the AKT inhibitor MK2206. Results:Cordycepin (50 mg/kg) significantly attenuated body weight loss and DAI elevation in DSS-treated mice. A total of 361 putative cordycepin-related targets were identified from six public databases, while 2, 072 UC-related targets were obtained from GeneCards, OMIM, and DisGeNET. A total of 199 overlapping targets were functionally enriched in processes including "TNF signaling pathway", "PI3K-AKT signaling pathway" and "cellular response to lipopolysaccharide". The PPI network identified 8 core targets, among which AKT1, NFKB1, RELA and TP53 demonstrated strong binding affinity (binding free energy<-6.0 kcal/mol) with cordycepin in molecular docking and were enriched within the PI3K/AKT pathway. IHC analysis showed that cordycepin reversed alterations of colonic AKT1 and ZO-1 levels in DSS mice. In Caco-2 cells, AKT inhibition with MK2206 attenuated the protective effects on tight junction integrity and mitochondrial function against LPS-induced injury. Conclusion:These findings suggest that prophylactic administration of cordycepin, a promising natural compound, alleviates experimental colitis, potentially through modulation of the PI3K/AKT1 signaling pathway and restoration of epithelial barrier integrity.

Colorectal cancer, ranking as the third most prevalent malignancy globally, substantially benefits from both immunotherapy and VEGF/VEGFR inhibitors. Nevertheless, the use of monotherapy proves inadequate in effectively tackling the heterogeneity of tumors and the intricacies of their microenvironment, frequently leading to drug resistance and immune evasion. This situation underscores the pressing need for innovative strategies aimed at augmenting the effectiveness and durability of treatments. Clinical research demonstrates that the combination of VEGF/VEGFR inhibitors (primarily including VEGF/VEGFR-targeted drugs and multi-kinase inhibitors) with immune checkpoint inhibitors creates a synergistic effect in the treatment of colorectal cancer. Our analysis explores how VEGF/VEGFR inhibitors recalibrate the tumor microenvironment, modulate immune cell functions, and influence the expression of immune checkpoints and cytokines. Furthermore, we critically evaluate the preclinical and clinical feasibility of these combined therapeutic approaches. Despite the potential for toxicity, the significant benefits and prospective applications of these strategies warrant thorough exploration. Exploring the synergistic mechanisms of these combined treatments has the potential to inaugurate a new paradigm in oncology, enabling more personalized and efficacious treatment modalities. Additionally, the synergy between VEGF/VEGFR inhibitors and nascent immunotherapies emerges as a promising field of inquiry.

Tumor heterogeneity and the complex immune microenvironment make it challenging to identify candidates for immunotherapy using dominant biomarkers. Tumor-infiltrating CD8+T cells, particularly CD103+CD8+ tissue-resident T cells and their specific subsets, are generally linked to better outcomes in many cancers, but their role in renal cancer remains largely unexplored. Here, we report that tumor-infiltrating CD103+CD8+hnRNPA2B1+ tissue-resident T cells can serve as an unfavorable prognostic factor for ccRCC patients and may be related to PD-1 treatment outcomes. We assessed the infiltration of CD103+CD8+T, CD103+CD8+hnRNPA2B1+T and other CD8+T cell subsets in ccRCC using multiplex immunofluorescence staining, and evaluated their links to patient clinicopathological features and prognosis. With published single-cell data from ccRCC patients treated with PD-1 therapy, we studied the expression differences of hnRNPA2B1 in tumor-infiltrating CD8+ T cells between responders and nonresponders. Compared with adjacent normal tissues, the infiltration levels of CD103+CD8+T, CD103+CD8+hnRNPA2B1+T cells, and CD103+CD8+Bhlhe40+T cells in ccRCC tissues were all significantly higher (all P values were <0.01). Moreover, patients with a higher degree of infiltration of these cells had worse overall survival (HR = 0.3490, 95% CI: 0.09338 to 1.304, P = 0.0144). All of them can serve as independent prognostic factors for ccRCC patients (HR = 3.753, 95% CI: 1.317 to 10.693, P = 0.013). Single-cell transcriptomics revealed that tumor-infiltrating CD8+T cells in patients responding to PD-1 antibody treatment had higher hnRNPA2B1 expression compared with nonresponders. In summary, our study indicates that tumor-infiltrating CD103+CD8+hnRNPA2B1+ tissue-resident T cells can serve as predictive factors and indicators for unfavorable prognosis and patient responses to PD-1 treatment outcomes in ccRCC patients.

The tumor microenvironment in colorectal cancer (CRC) is marked by a diverse and abundant population of cancer-associated fibroblasts (CAFs), which play a crucial role in radioresistance. Nonetheless, the mechanisms through which CAFs contribute to radioresistance remain unclear. In this study, we demonstrate that CAFR, a specific subset of CAFs derived from radioresistant CRC patients, produces higher levels of transforming growth factor-β1 (TGF-β1) compared to CAFs isolated from radiosensitive CRC patients. Through long noncoding RNA (lncRNA) profiling of tumor cells treated with CAF-conditioned medium (CAF-CM), we identify WARS2-IT1 (WARS2 intronic transcript 1), whose expression is directly stimulated by TGF-β1 signaling. This lncRNA serves as a key player in promoting radioresistance and is essential for the TGFβ1-induced radioresistance pathway. Mechanistically, WARS2-IT1 interferes with the interaction between prolyl hydroxylase domain 2 (PHD2) and hypoxia-inducible factor-1α (HIF-1α), preventing the hydroxylation and subsequent degradation of HIF-1α. This process leads to the activation of glycolytic pathways, thereby enhancing radioresistance. Our findings underscore the potential of targeting CAF-driven WARS2-IT1 as a promising strategy to counteract tumor radioresistance in CRC.

This study aimed to clarify the clinical significance of ARID1A expression in gastric cancer (GC) and explore its mechanistic role in regulating PD-L1 expression during immunotherapy response. A comprehensive analysis of ARID1A expression was conducted in 205 gastric adenocarcinoma specimens and 30 matched paracancerous tissues. ARID1A and PD-L1 expression profiles were assessed through immunohistochemical analysis. Functional studies using ARID1A-depleted GC cell lines were performed to uncover the underlying molecular mechanisms, with a particular focus on the PI3K/AKT signaling pathway. ARID1A deficiency was predominantly observed in GC tissues (42.4

BACKGROUND:To explore the associations of age, intramuscular adipose tissue index (IATI), and serum albumin with survival status in initial dialysis patients and the mediating effects. METHODS:Totally 1,044 Chinese initial dialysis patients from four hospitals (2014-2020) were eventually enrolled and followed up to December 31, 2022 or until death in this retrospective cohort study. IATI was defined as the ratio of low attenuation muscle density to skeletal muscle density assessed by CT at the first lumbar vertebra level. Multivariate Cox regression and two-piecewise Cox proportional hazards models were used to determine the risk factors for all-cause mortality and to perform stratified analysis. Mediation analysis was conducted to identify mediators. RESULTS:High IATI, age > 60 years, and low serum albumin were significant independent risk factors for all-cause mortality. The association between IATI and all-cause mortality remained significant in female patients, and those with low neutrophil/lymphocyte ratios, or without coronary heart disease. When age and IATI were categorical variables, age had a significant indirect effect on all-cause mortality (0.015) and survival time (-1.262) via IATI, while IATI indirectly influenced all-cause mortality through serum albumin (0.012). CONCLUSIONS:Age > 60 years and high IATI are risk factors for all-cause mortality while serum albumin is protective in initial dialysis patients. The relationship between age and survival status may be mediated by IATI, while the effect of IATI on all-cause mortality may be mediated by serum albumin.

Bilirubin metabolism crucially maintains normal liver function, but whether it contributes to antiviral immunity remains unknown. Here, we reveal that the liver bilirubin metabolic pathway facilitates antiviral innate immunity of the body. We discovered that viral infection upregulates uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) expression in the liver, which in turn stabilizes IRF3 proteins to promote type I interferon (IFN-I) production. Moreover, we found that serum unconjugated bilirubin (UCB), a unique physiological substrate of UGT1A1, can competitively inhibit the binding of IFN-I to IFN-I receptor 2 (IFNAR2), thus attenuating IFN-I-induced antiviral signaling of the body. Accordingly, effective bilirubin metabolism in the liver promotes antiviral immunity of the body by specifically employing liver UGT1A1-mediated enhancement of IFN-I production and reducing serum bilirubin-mediated inhibition of IFN-I signaling. This study uncovers the significance of bilirubin metabolism in antiviral innate immunity and demonstrates that conventional IFN-I therapy is less efficient for patients with hepatitis B virus (HBV) with high levels of bilirubin.

Cancer-associated fibroblasts (CAFs) are key regulators in tumor microenvironment and tumor immunity, partly through MHC-II expression that modulates T-cell differentiation. However, the upstream cytokine signals controlling MHC-II expression in fibroblasts still remain poorly defined. We examined MHC-II expression on fibroblasts under stimulation with interferon-γ (IFN-γ) and interleukin-1β (IL-1β) by using flow cytometry, transcriptomic analysis, and qRT-PCR. To dissect transcriptional regulation, we generated CIITA-overexpressing and CIITA-deficient fibroblast lines by lentiviral transduction and CRISPR/Cas9-mediated editing. Public scRNA-seq, ATAC-seq, and ChIP-seq datasets were further analyzed to validate molecular mechanisms. IFN-γ robustly up-regulated MHC-II expression on fibroblasts, while IL-1β selectively suppressed this induction without affecting PD-L1. Mechanistically, IL-1β attenuated IFN-γ–induced CIITA expression at the mRNA level but did not alter STAT1 abundance or phosphorylation. Functional assays confirmed that CIITA was indispensable for IFN-γ–driven MHC-II expression in fibroblasts. Integration of transcriptomic and epigenomic data demonstrated that CIITA directly bound MHC-II gene promoters and regulated chromatin accessibility. Our study identifies an IFN-γ/STAT1/CIITA axis as the central regulator of MHC-II expression in fibroblasts and reveals IL-1β as a potent suppressor of this pathway. These findings highlight a novel cytokine-mediated regulatory mechanism underlying CAF-driven immunosuppression within the tumor microenvironment.