Chitinase-3-like-protein 1 (CHI3L1), a low-abundance protein in normal tissues, is markedly upregulated in the pancreatic tumor microenvironment (TME), where it promotes fibrosis and immune evasion. Spatial transcriptomics revealed enrichment of CHI3L1 at tumor-stroma interfaces, suggesting that cell-cell interactions regulate CHI3L1 expression. We employed 2D and 3D multicellular culture models, incorporating pancreatic cancer cells, macrophages, and pancreatic stellate cells (PSCs), to recapitulate TME-mediated CHI3L1 induction. Mechanistic insights were gained through secretome profiling, chromatin immunoprecipitation (ChIP), and methylation-specific PCR. The therapeutic potential of targeting identified axes was evaluated in an orthotopic pancreatic adenocarcinoma (PDAC) mouse model. We identified CCL2, CXCL10, and SPARC as key secreted mediators during tumor-stroma crosstalk that cooperatively induced CHI3L1 expression in cancer cells via activation of NF-κB and STAT3. Specifically, inflammatory cytokines within the TME recruited macrophages to induce CCL2, which, in concert with PSCs, enhances CXCL10 and SPARC secretion. Mechanistically, NF-κB directly bound the CHI3L1 promoter, while STAT3 reduced DNA methyltransferase 1 levels, leading to promoter hypomethylation and epigenetic activation of CHI3L1. Clinically, high CHI3L1 expression correlated with the upregulated stromal CCL2, CXCL10, and SPARC levels, and the combined four-marker signature was an independent prognostic factor for both overall and disease-free survival in multivariable analysis. In vivo, blockade of the upstream stromal pathways (CCR2/CXCR3/TGFβR1) coupled with CHI3L1 neutralization reduced tumor growth and remodeled the immunosuppressive microenvironment in immunocompetent PDAC models. Our findings uncover a cooperative multicellular signaling network that orchestrates CHI3L1 expression in cancer via transcriptional and epigenetic reprogramming. Disrupting these upstream stromal pathways concurrently with CHI3L1 neutralization was associated with reduced T-cell exhaustion, offering a promising combinatorial approach for PDAC immunotherapy.
Primary cilia are microtubule-based organelles protruding from the cell surface, which are conventionally understood as passive cellular antennae that detect extracellular stimuli. However, emerging evidence redefines these microtubule-based organelles as dynamic, bidirectional hubs that integrate environmental sensing with cellular metabolic adaptation. By selectively compartmentalizing receptors, ion channels, transporters, and signaling components, they function as specialized signal-processing compartments that receive, integrate, amplify, and relay information to coordinate cellular metabolism, adaptation, and cell-fate determination. Cilia-dependent signaling pathways regulate glucose and lipid metabolism, Ca2⁺ and second-messenger dynamics, and mitochondrial homeostasis. Conversely, environmental and metabolic changes remodel ciliary structure, molecular composition, and signaling competence. In this review, we present primary cilia as a bidirectional interface between environmental sensing and metabolic adaptation. We discuss how cilia respond to nutrient availability, mechanical forces, and oxygen tension, and how disruption of this sensory-metabolic interface contributes to metabolic, cardiovascular, reproductive, neurodegenerative, and cancer-related diseases. Defining the cellular and environmental contexts in which ciliary remodeling is protective or pathogenic will be essential for translating cilia biology into therapeutic strategies.
Approximately one-third of people with diabetes have diabetic kidney disease (DKD), and DKD remains a leading cause of kidney failure in the United States. DKD is characterized by injury to the glomerular filtration barrier and renal tubulointerstitium, arising from complex and convergent metabolic, hemodynamic, and inflammatory insults. Tyrosine phosphorylation, a reversible post-translational modification, is a central regulatory mechanism in these pathways and is dynamically controlled by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Aberrant tyrosine phosphorylation is a hallmark of DKD and implicates PTPs as key modulators of podocyte, endothelial, tubular, and immune cell dysfunction. Over 100 genes code for PTPs in humans, with 38 ‘classical’ PTPs that specifically target tyrosine motifs, including receptor-type and non-receptor-type subtypes. Several classical PTPs are implicated in DKD pathogenesis, while others are increasingly associated with signaling cascades that drive renal metabolism, inflammation, fibrosis, and cell death. There is growing interest in PTPs as their contributions to the disease emerge, though the role(s) of some remain uncharacterized in DKD. Moreover, recent breakthroughs in pharmaceuticals targeting PTPs for metabolic diseases and cancer have ignited interest in repurposing or tailoring PTP‑directed therapeutics for DKD. This review summarizes current knowledge and recent advances of classical PTPs in DKD, including their roles in insulin signaling, cellular architecture, and glomerular and tubular cell injury. It further discusses existing DKD treatments and highlights emerging strategies to pharmacologically modulate PTP activity, such as active‑site inhibitors, allosteric agents, and antibody‑targeting approaches. By integrating mechanistic insights with drug discovery efforts, this review outlines how targeting specific PTPs could complement current standard‑of‑care therapies and open new avenues for precision treatment of DKD.
Personalized neoantigen cancer vaccine is a promising strategy for precision immunotherapy by targeting patient-specific and mutation-derived tumor antigens. Early clinical studies have demonstrated the feasibility, safety, and immunogenicity of these vaccines across multiple solid tumors, with encouraging outcomes particularly when combined with immune checkpoint blockade. However, broader clinical translation remains limited by sequential bottlenecks across the vaccine development pipeline, including false-positive neoantigen selection, imperfect modeling of antigen processing and HLA presentation, limited prediction of T-cell receptor recognition, and challenges in formulation, delivery, and manufacturing. Artificial intelligence and advanced computational workflows are increasingly integrated into this pipeline to improve candidate prioritization and support more reproducible decision-making. In this review, we summarize clinical progress and key translational barriers in personalized neoantigen vaccination, and discuss how AI-enabled approaches may contribute across four major stages: multi-omics integration for neoantigen discovery, processing-aware HLA presentation prediction, structure-aware and TCR-informed immunogenicity modeling, and data-driven formulation optimization, particularly for lipid nanoparticle-based delivery systems. These approaches are able to help narrow biological and chemical search spaces, improve prioritization, and provide mechanistic insights into antigen presentation and immune recognition rather than replacing experimental validation. This articlefurther addresses future implementation challenges, including dataset diversity, model interpretability, prospective benchmarking, manufacturing traceability, and evolving regulatory frameworks for individualized mRNA cancer immunotherapies. Integrating computational innovation with rigorous immunological validation, scalable manufacturing, and regulatory oversight will be essential for advancing personalized neoantigen vaccines toward broader clinical implementation.
Cardiac fibrosis is a pathological remodeling process that contributes to the development and progression of heart failure. Although glucose-dependent insulinotropic polypeptide (GIP) may exert antifibrotic effects, how GIP receptor activation regulates cardiac fibrogenesis and modulates cardiac function in heart failure remains unclear. This study investigated whether GIP receptor agonism suppresses cardiac fibroblast activity and improves heart failure and explored the underlying mechanisms by using cellular and animal models. Human cardiac fibroblasts were treated with [D-Ala2]GIP (DA-GIP; 10, 100, or 300 nM) for 24 h or left untreated (control). Fibroblast migration, collagen production, and intracellular signaling were examined using wound healing, immunoblotting, enzyme-linked immunosorbent, and fluorometric assays. Cardiac structure, function, and fibrosis were assessed through echocardiography and Masson’s trichrome staining in rats with isoproterenol-induced heart failure with and without DA-GIP (24 nM/kg, twice daily for 2 weeks) administration. Compared with control cells, DA-GIP (300 nM)-treated cardiac fibroblasts exhibited a significantly lower migratory activity and reduced expression levels of pro-collagen IA1, pro-collagen III, and transforming growth factor-β1 proteins. Additionally, DA-GIP increased nitric oxide (NO) production and promoted endothelial NO synthase (eNOS) and protein kinase B (Akt) activation in cardiac fibroblasts. Notably, Akt inhibition blocked DA-GIP-induced eNOS activation, and treatment with Nω-nitro-L-arginine methyl ester (a NO synthase inhibitor, 100 μM) attenuated the antifibrotic effect of DA-GIP. In heart failure rats, DA-GIP reduced myocardial fibrosis, chamber dilatation, and systolic dysfunction. DA-GIP suppresses cardiac fibroblast activity through Akt-dependent eNOS activation and subsequent NO production, thereby improving cardiac remodeling and function in experimental heart failure.
