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Inflammatory bowel disease (IBD) is typically diagnosed after the onset of symptoms in the context of established, characteristic patterns of intestinal inflammation. However, there is now substantial evidence pointing to a prolonged, biologically active preclinical phase of disease. Analysis of archived biological samples from large-scale longitudinal cohort studies of healthy individuals, some of whom develop incident IBD, has identified different molecular features that can be detected many years before clinical presentation. These include increased titres of antimicrobial and autoreactive antibodies and perturbations in a complex network of circulating, immunologically active proteins. As well as affording 'diagnostic' opportunities to identify individuals destined to develop IBD, an integrated view of these multiple different molecular features enables speculation of potential proximal drivers of preclinical IBD. Consistently recognised associations include dysregulated mononuclear phagocyte-lymphocyte interactions, augmented chemotaxis, frequently relating to interferon-γ-driven chemokine programmes and evidence of early tissue injury, such as increased circulating extracellular matrix components and metalloproteinases. Increased levels of circulating antibacterial and antiviral antibody responses hint towards disordered host-microbe interactions as potential prime triggers for the transition between health and early disease, although it is possible that these serological responses are an epiphenomenon linked to early mucosal damage and microbial translocation. There is now a timely opportunity to develop these different molecular features into scalable and clinically tractable biomarker panels to detect preclinical disease and enable strategies to proactively intercept IBD before it even develops.

Background: Capillarisation of liver sinusoidal endothelial cells (LSECs) constitutes an early pathological event that promotes hepatic stellate cell activation and initiates liver fibrogenesis. Previous studies suggest that Ras-associated protein 1A (RAP1A) might be involved in liver fibrosis. However, the role of RAP1A in LSEC capillarisation remains unclear.

Objective: This study aimed to investigate the role of the endothelial GTPase RAP1A in sinusoidal capillarisation and liver fibrosis.

Design: Liver fibrosis models were induced by HFHCD, CDAHFD, CCl₄ or DDC treatment. EC-specific Rap1a knockout (Rap1a ^ΔEC) mice were generated by breeding Rap1a ^fl/fl mice with Cdh5-Cre mice. Therapeutic intervention was performed using the RAP1 activator 8-pCPT-2'-O-Me-cAMP. LSEC capillarisation, along with the extent of liver fibrosis and inflammation, was evaluated.

Results: RAP1A expression in LSECs was downregulated in all murine fibrosis models, as well as in primary LSECs undergoing spontaneous capillarisation during in vitro culturing. Young Rap1a ^ΔEC mice exhibited spontaneous capillarisation, which progressed to liver fibrosis with age. Endothelial Rap1a deficiency exacerbated sinusoidal capillarisation and liver fibrosis in CCl₄-/DDC-treated mice. Mechanistically, RAP1A loss promoted RAF1 degradation via the ubiquitin-proteasome pathway, enhancing nuclear translocation of Notch intracellular domain (NICD) and activating Notch signalling. Pharmacological activation of RAP1A attenuated LSEC capillarisation and mitigated liver fibrosis in CCl₄-/DDC-induced models.

Conclusion: Endothelial Rap1a deficiency aggravates capillarisation and liver fibrosis by activating Notch signalling through RAF1 degradation. These findings indicate that Rap1a is essential for maintaining LSEC homeostasis and represents a potential intervention target for liver fibrosis.

Background: As it is a tumour-associated antigen in epithelial cells, research on claudin18.2 (CLDN18.2) has focused on its role as a therapeutic target in pancreatic cancers and its part in maintaining tight junctions.

Objective: We elucidate the role of trogocytosis-related CLDN18.2 in CD8⁺ T cells and pancreatic ductal adenocarcinoma (PDAC) progression.

Design: We constructed humanised hCD34⁺, Trp53^R172HKras^G12DPdx1-cre (KPC), Cldn18.2 knockout (KO), and patient-derived xenograft/organoid mouse models. Flow cytometry, immunofluorescence, single-cell RNA-sequencing and immunoprecipitation-mass spectrometry (IP-MS) were performed.

Results: CLDN18.2⁺CD8⁺ T cells indicated poor pancreatic cancer prognosis and immunotherapeutic resistance. CD8⁺ T cells acquired CLDN18.2 from tumour cells via trogocytosis, inhibiting their activation and cytotoxicity. "Dressed" CLDN18.2 suppressed glucose uptake, glycolysis and cytotoxicity of tumour-infiltrating CD8⁺ T cells. Mechanically, trogocytosis-related CLDN18.2 induced GSK3β/CK1α-mediated β-catenin phosphorylation, promoting β-catenin ubiquitination and proteasome degradation in CD8⁺ T cells. CLDN18.2 interacted with β-catenin's N-terminal domain via its C-terminal domain, further strengthening the interaction between β-catenin and CK1α. Moreover, CLDN18.2⁺CD8⁺ T cells preferentially 'homed' to the bone marrow through the CXCL12/CXCR4 axis, skewed haematopoietic stem cell myeloid differentiation and induced systemic immune senescence via IL1α. Notably, preclinical mouse studies showed PC18.1 peptide sensitised immunotherapy and suppressed PDAC progression by disrupting the CLDN18.2/β-catenin interaction in CD8⁺ T cells.

Conclusions: Trogocytosis-related CLDN18.2 inhibited the glucose uptake, glycolysis and cytotoxicity of tumour-infiltrating CD8⁺ T cells by promoting the ubiquitin-proteasomal degradation of β-catenin in PDAC. Therefore, targeting trogocytosis-related CLDN18.2⁺CD8⁺ T cells may be a promising therapeutic strategy to inhibit PDAC progression.

Background: Cancer-associated fibroblasts (CAFs) are key stromal components of the tumour microenvironment (TME) that profoundly influence tumour progression. However, CAFs exhibit pronounced phenotypic and functional heterogeneity, and whether conserved CAF subtypes with shared functional hallmarks exist across different cancer types remains unclear.

Objective: We sought to uncover universal CAF subtypes that transcend tumour origins, defining their core molecular signatures and pro-tumorigenic functions within the TME.

Design: We constructed a pan-cancer CAF atlas through single-cell transcriptomic analysis of 554 specimens across 14 cancer types. To validate the findings, we performed further functional analyses, including in vitro migration and invasion assays, in vivo lymphatic metastasis models and mechanistic studies focusing on candidate signalling pathways.

Results: We identified a conserved syndecan 1 (SDC1) ⁺ CAF subset associated with advanced tumour stage and poor outcomes. These CAFs enhanced tumour cell migration and invasion in vitro and promoted lymphatic metastasis in vivo. This effect is mediated through connective tissue growth factor (CTGF) secretion, which activates fibroblast growth factor receptor 3 (FGFR3) signalling in tumour cells to induce epithelial-mesenchymal transition (EMT). Blocking CTGF or FGFR3 signalling abrogated these effects. We also found that kruppel like factor 6 (KLF6) directly regulates CTGF in SDC1⁺ CAFs, establishing a complete KLF6-CTGF-FGFR3 metastatic axis.

Conclusions: Our study establishes SDC1⁺ CAFs as a universal, metastasis-promoting CAF subset across multiple cancer types and uncovers a novel KLF6-CTGF-FGFR3 axis that drives EMT and tumour dissemination. These findings provide mechanistic insight into CAF-tumour cell crosstalk and highlight actionable stromal targets for anti-metastatic therapies across diverse malignancies.

The gut microbiota plays a crucial role in regulating host immunity, metabolism and inflammation, with accumulating evidence linking its composition and function to the development and progression of cancers in the reproductive tract. Patients with ovarian, endometrial and cervical cancers exhibit distinct alterations in their gut microbiota, characterised by reduced microbial diversity and shifts towards taxa associated with dysbiosis and chronic inflammation. Mechanistically, gut-derived metabolites and microbial translocation appear to influence systemic immune responses and oestrogen metabolism, thereby fostering a tumour microenvironment conducive to cancer growth. Beyond its role in tumourigenesis, the gut microbiota also affects treatment outcomes. Dysbiosis can reduce sensitivity to chemotherapy and alter immunotherapy responses, while antibiotic use during cancer treatment has been linked to poorer prognosis. Clinically, these insights highlight emerging applications of microbiome modulation as biomarkers for patient stratification and as adjuvant approaches to enhance therapeutic efficacy in gynaecological oncology, underscoring the therapeutic potential of targeting the microbiota-through dietary interventions, probiotics or faecal microbiota transplantation-to improve cancer treatment outcomes. However, most of these applications remain investigational, and current evidence is limited by heterogeneity across study designs, patient cohorts and cancer subtypes. This review summarises current understanding of gut microbiota profiles in reproductive tract cancers, examines potential mechanisms by which the microbiota influences malignancy, discusses its impact on therapy response and explores its emerging role in precision oncology.

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterised by a dismal prognosis and insensitivity to immune checkpoint blockers (ICBs); however, the underlying mechanism remains elusive.

Objective: This study aimed to identify tumour cell-intrinsic regulators that promote immune evasion and ICB resistance in PDAC.

Design: Multi-omics analysis and clinical cohort studies identified protein disulfide isomerase family A member 6 (PDIA6) as a regulator of the immune microenvironment. Flow cytometry, multiplex immunohistochemistry, electron microscopy and Glutathione S-Transferase (GST) pulldown assays confirmed that PDIA6 repressed PRKR-like endoplasmic reticulum kinase (PERK) activation and immunogenic cell death (ICD). Chromatin immunoprecipitation confirmed that KRAS^G12D and YY1 modulated PDIA6 transcription. LSL-Kras ^G12D/+ ;LSL-Trp53 ^R172H/+ ;Pdx-1-Cre (KPC) mouse models showed that PDIA6 inhibition improved ICB response.

Results: Multi-omics screening identified PDIA6 as a biomarker of CD8⁺ T-cell paucity and poor prognosis in patients with PDAC. High PDIA6 levels predicted poor ICB response in the PDAC cohorts. PDIA6 inhibition reprogrammed the immunosuppressive tumour microenvironment and hindered mouse PDAC growth in the presence of CD8⁺ T-cell, which is attributed to enhanced ICD. PDIA6 interacted with cysteine 453 of PERK, abrogating the disulphide bond-mediated dimerisation and activation of PERK, an ICD inducer. Oncogenic KRAS^G12D potently upregulated PDIA6 via YY1-mediated transcriptional activation. We identified a small-molecule inhibitor of PDIA6, PACMA31, and demonstrated that targeting PDIA6 with PACMA31 improved ICB efficacy in a PDAC mouse model with KRAS mutations.

Conclusions: PDIA6, driven by KRAS^G12D, alleviates ICD and promotes immune evasion, functioning as a predictive biomarker to screen ICB-sensitive patients and a therapeutic target to improve ICB efficacy in PDAC with KRAS mutations.

Background: Plasmablast-derived HBV surface antigen (HBsAg)-specific monoclonal antibody (mAb) and structural basis for binding to native HBsAg are poorly known.

Objective: We aimed to identify plasmablast-derived HBsAg-specific mAbs, evaluate their antiviral activities and resolve their structure for binding to native HBsAg.

Design: A previously vaccinated volunteer was enrolled in this study, who was boosted with a dose of recombinant hepatitis B vaccine and donated the blood sample. Activated plasmablasts were sorted from fresh peripheral blood mononuclear cells and mAbs were expressed. Their gene features, cross-genotypic binding activities and antiviral functions in vitro and in vivo were comprehensively analysed. The cryo-electron microscopy (cryo-EM) was used to determine the structure of representative mAb bound to the native HBsAg.

Results: In this study, we cloned a series of HBsAg-specific mAbs directly from clonally expanded plasmablasts from a vaccinated individual. Most of the mAbs displayed cross-reactivities of binding to different genotype HBsAg proteins and antiviral functions such as neutralisation and antibody-dependent cellular phagocytosis. These human anti-HBsAg mAbs, especially SY-4-class and SY-23-class, could be good candidates for antibody drugs. The cryo-EM structure of SY-23 bound to the dimeric HBsAg was determined, revealing its binding mechanism and unprecedented structural detail of the major antigenic loop (AGL) of HBsAg.

Conclusion: Overall, our work has uncovered the diverse gene features and varied anti-HBV activities of plasmablast-derived mAbs, providing a series of antibody drug candidates and the long-sought-after atomic model of AGL has paved the way for a wholistic characterisation of the AGL's dynamic conformation during HBV infection and immune response.

Background: Gastric cancer (GC) is one of the most common malignancies worldwide and it is the third leading cause of cancer-related death in China. While Helicobacter pylori is a known GC pathogen, its abundance declines in tumours and the role of other bacteria in GC metastasis remains unclear.

Objective: We aim to investigate the mechanisms of other bacteria influencing GC progression and metastasis.

Design: Integrated intratumoural microbiome-metabolome analysis identified GC-associated microbes and metabolites. We then demonstrated the pro-metastatic role of Acinetobacter baumannii (A. baumannii, Ab) and its metabolite nicotinic acid (NA) using genetic, molecular and in vivo approaches.

Results: The abundance of A. baumannii was significantly increased in GC tissues, correlating with advanced tumour stage and intratumoural NA levels. Fluorescence in situ hybridisation confirmed its colonisation in GC tumours. In co-culture systems, A. baumannii increased NA levels, enhancing nicotinamide adenine dinucleotide (NAD) metabolism and increasing 1-Methylnicotinamide accumulation in tumour cells. Mutagenesis of the bacterial NA synthase gene pncA confirmed that A. baumannii excreted an NA-dependent pro-metastasis effect. Mechanically, A. baumannii promotes GC metastasis by reprogramming tumour cell glucose metabolism, reducing oxidative phosphorylation while enhancing glycolysis and activating the hypoxia-inducible factor-1 pathway in GC cells through metabolites both in vivo and in vitro.

Conclusions: This study elucidates the role of A. baumannii in enhancing NAD metabolism in GC cells through NA synthesis, consequently promoting GC metastasis. These findings establish a microbiota-metabolism axis as a mechanistic foundation for developing targeted therapeutic strategies against GC metastasis.