Liver metastasis is the leading cause of mortality in patients with colorectal cancer. Given the significance of both epithelial–mesenchymal transition (EMT) of tumor cells and the immune microenvironment in colorectal cancer liver metastasis (CRLM), the interplay between them could hold the key for developing improved treatment options. We employed multiomics analysis of 130 samples from 18 patients with synchronous CRLM integrated with external datasets to comprehensively evaluate the interaction between immune cells and EMT of tumor cells in liver metastasis. Single-cell RNA sequencing analysis revealed distinct distributions of nonmalignant cells between primary tumors from patients with metastatic colorectal cancer (mCRC) and non-metastatic colorectal cancer, showing that Th17 cells were predominantly enriched in the primary lesion of mCRC. TWEAK, a cytokine secreted by Th17 cells, promoted EMT by binding to receptor Fn14 on tumor cells, and the TWEAK–Fn14 interaction enhanced tumor migration and invasion. In mouse models, targeting Fn14 using CRISPR-induced knockout or lipid nanoparticle–encapsulated siRNA alleviated metastasis and prolonged survival. Mice lacking Il17a or Tnfsf12 (encoding TWEAK) exhibited fewer metastases compared with wild-type mice, while cotransfer of Th17 with tumor cells promoted liver metastasis. Higher TWEAK expression was associated with a worse prognosis in patients with colorectal cancer. In addition, CD163L1+ macrophages interacted with Th17 cells, recruiting Th17 via the CCL4-CCR5 axis. Collectively, this study unveils the role of immune cells in the EMT process and identifies TWEAK secreted by Th17 as a driver of CRLM. Significance: TWEAK secreted by Th17 cells promotes EMT by binding to Fn14 on colorectal cancer cells, suggesting that blocking the TWEAK–Fn14 interaction may be a promising therapeutic approach to inhibit liver metastasis.

Dectin-1 (gene Clec7a), a receptor for β-glucans, plays important roles in the host defense against fungi and immune homeostasis of the intestine. Although this molecule is also suggested to be involved in the regulation of tumorigenesis, the role in intestinal tumor development remains to be elucidated. In this study, we find that azoxymethane-dextran-sodium-sulfate-induced and Apc^Min-induced intestinal tumorigenesis are suppressed in Clec7a^−/− mice independently from commensal microbiota. Dectin-1 is preferentially expressed on myeloid-derived suppressor cells (MDSCs). In the Clec7a^−/− mouse colon, the proportion of MDSCs and MDSC-derived prostaglandin E₂ (PGE₂) levels are reduced, while the expression of IL-22 binding protein (IL-22BP; gene Il22ra2) is upregulated. Dectin-1 signaling induces PGE₂-synthesizing enzymes and PGE₂ suppresses Il22ra2 expression in vitro and in vivo. Administration of short chain β-glucan laminarin, an antagonist of Dectin-1, suppresses the development of mouse colorectal tumors. Furthermore, in patients with colorectal cancer (CRC), the expression of CLEC7A is also observed in MDSCs and correlated with the death rate and tumor severity. Dectin-1 signaling upregulates PGE₂-synthesizing enzyme expression and PGE₂ suppresses IL22RA2 expression in human CRC-infiltrating cells. These observations indicate a role of the Dectin-1-PGE₂-IL-22BP axis in regulating intestinal tumorigenesis, suggesting Dectin-1 as a potential target for CRC therapy.

Lung adenocarcinoma (LUAD) is the most prevalent and aggressive subtype of lung cancer, exhibiting a dismal prognosis with a five-year survival rate below 5%. DEAD-box RNA helicase 18 (DDX18, gene symbol DDX18), a crucial regulator of RNA metabolism, has been implicated in various cellular processes, including cell cycle control and tumorigenesis. However, its role in LUAD pathogenesis remains elusive. This study demonstrates the significant upregulation of DDX18 in LUAD tissues and its association with poor patient survival (from public databases). Functional in vivo and in vitro assays revealed that DDX18 knockdown potently suppresses LUAD progression. RNA sequencing and chromatin immunoprecipitation experiments identified cyclin-dependent kinase 4 (CDK4), a cell cycle regulator, as a direct transcriptional target of DDX18. Notably, DDX18 depletion induced G1 cell cycle arrest, while its overexpression promoted cell cycle progression even in normal lung cells. Interestingly, while the oncogenic protein c-Myc bound to the DDX18 promoter, it did not influence its expression. Collectively, these findings establish DDX18 as a potential oncogene in LUAD, functioning through the CDK4-mediated cell cycle pathway. DDX18 may represent a promising therapeutic target for LUAD intervention.

Neuregulin-1 (Nrg1, gene symbol: Nrg1), a ligand of the ErbB receptor family, promotes intestinal epithelial cell proliferation and repair. However, the dynamics and accurate derivation of Nrg1 expression during colitis remain unclear. By analyzing the public single-cell RNA-sequencing datasets and employing a dextran sulfate sodium (DSS)-induced colitis model, we investigated the cell source of Nrg1 expression and its potential regulator in the process of epithelial healing. Nrg1 was majorly expressed in stem-like fibroblasts arising early in mouse colon after DSS administration, and Nrg1–Erbb3 signaling was identified as a potential mediator of interaction between stem-like fibroblasts and colonic epithelial cells. During the ongoing colitis phase, a significant infiltration of macrophages and neutrophils secreting IL-1β emerged, accompanied by the rise in stem-like fibroblasts that co-expressed Nrg1 and IL-1 receptor 1. By stimulating intestinal or lung fibroblasts with IL-1β in the context of inflammation, we observed a downregulation of Nrg1 expression. Patients with inflammatory bowel disease also exhibited an increase in NRG1⁺IL1R1⁺ fibroblasts and an interaction of NRG1–ERBB between IL1R1⁺ fibroblasts and colonic epithelial cells. This study reveals a novel potential mechanism for mucosal healing after inflammation-induced epithelial injury, in which inflammatory myeloid cell-derived IL-1β suppresses the early regeneration of intestinal tissue by interfering with the secretion of reparative neuregulin-1 by stem-like fibroblasts.

Objective: To evaluate the effectiveness of perioperative non-drug interventions in reducing postoperative pulmonary complications (PPCs) in adults undergoing abdominal surgery. Design: Systematic review and meta-analysis. Data sources: Ovid MEDLINE, Embase, and Web of Science from database inception to January 2025 and updated in January 2026, with no language restrictions. Study selection: Randomised controlled trials assessing the effectiveness of perioperative non-drug interventions for the prevention of PPCs in adults undergoing elective abdominal surgery under general anaesthesia, with clearly defined PPCs. Main outcome measures: The primary outcome was the proportion of patients developing PPCs. Secondary outcomes included the proportion of patients with PPC subtypes according to European Perioperative Clinical Outcome definitions (respiratory infection, respiratory failure, pleural effusion, atelectasis, or pneumothorax) and hospital length of stay. Data extraction and synthesis: Two reviewers independently screened studies, extracted data, and assessed risk of bias with the Cochrane RoB 2.0 tool. Data were synthesised using meta-analyses and trial sequential analyses, with the evidence certainty assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Results: 255 trials including 55 260 participants were included, evaluating 10 types of interventions with 39 subtypes for PPC prevention. PPCs occurred in 6467 (11.7%) participants across all included trials. High certainty evidence showed that low fraction of inspired oxygen (FiO ₂ ) significantly reduced PPCs (risk ratio 0.81, 95% confidence interval 0.71 to 0.92). Moderate certainty evidence showed benefit for four intervention types: lung protective ventilation (risk ratio 0.66, 0.57 to 0.76), physiotherapy (0.55, 0.46 to 0.65), analgesia (0.73, 0.64 to 0.84), and nutrition (0.74, 0.63 to 0.87), with individualised positive end expiratory pressure, composite lung protective ventilation, early mobilisation, and epidural analgesia also showing benefit at the subtype level. Trial sequential analysis confirmed sufficient cumulative evidence for all the above interventions except early mobilisation. By contrast, goal directed haemodynamic therapy, targeted blood pressure management, restrictive fluid therapy, and postoperative bi-level positive airway pressure showed no evidence of benefit, with moderate certainty. Conclusions: This synthesis establishes an evidence hierarchy for PPC prevention in abdominal surgery. Low FiO ₂ is the only intervention supported by high certainty evidence and should be prioritised in clinical practice. Other beneficial strategies include lung protective ventilation, physiotherapy, analgesic techniques, and nutrition interventions. Conversely, the role of goal directed haemodynamic therapy—despite its widespread use—warrants reconsideration for PPC prevention. These findings facilitate prioritisation of effective interventions and development of evidence based guidelines. Study registration: PROSPERO CRD42025637449.