Transglutaminases in Cancer Progression: Mechanisms, Microenvironment, and Therapeutic Opportunities

Transglutaminases (TGs) are a family of calcium-dependent acyltransferases — TG1–TG7 and Factor XIIIa — best known for catalyzing protein cross-linking through ε-(γ-glutamyl)lysine isopeptide bonds. Initially studied for their structural roles in tissue stabilization and wound healing, TGs are now recognised as important regulators of cancer biology. Tissue transglutaminase (TG2), in particular, is a multifunctional protein that acts as a cross-linking enzyme, a GTP-binding signaling protein, a cell-surface adhesion co-receptor for fibronectin and β-integrins, and a molecular scaffold coordinating intracellular survival pathways. Its transition between a closed, GTP-bound conformation and an open, catalytically active conformation links metabolic and redox conditions directly to cell fate.In tumors, this functional versatility enables TG2 to influence multiple stages of disease progression. TG2 has been implicated in epithelial–mesenchymal transition, cancer stem cell maintenance, NF-κB and TGF-β signaling, autophagy, metastatic dissemination, and resistance to chemotherapy and targeted agents. At the chromatin level, TG2 has emerged as a histone-modifying enzyme: it catalyzes histone H3 glutamine-5 monoaminylation, including serotonylation, generating epigenetic marks associated with transcriptionally permissive chromatin and increasingly implicated in cancer-associated chromatin architecture and oncogenic transcriptional programs. Conversely, TGM2 expression itself is subject to epigenetic regulation through promoter DNA methylation and changes in chromatin accessibility, underscoring a bidirectional relationship between TG2 and the cancer epigenome. Beyond tumor-intrinsic signaling, extracellular TG2 binds fibronectin and facilitates its association with β-integrins, thereby translating matrix-derived signals into oncogenic programs that promote adhesion, survival, stemness, and therapeutic resistance. TG2 can also remodel the extracellular matrix, alter stromal organization, and influence cancer-associated fibroblasts and infiltrating immune cells, placing it at the intersection of desmoplasia, immune regulation, and metastasis. Importantly, its effects remain highly context-dependent: TG2 may promote survival and progression in one tumor setting while supporting differentiation or cell death in another. Resolving this functional duality is essential for developing effective therapeutic strategies. Therapeutic interest in TG2 is consequently accelerating. Irreversible and reversible small-molecule inhibitors, allosteric modulators, peptidomimetics, and antibody-based strategies are being investigated, while insights gained from therapies designed for celiac disease and fibrosis are actively guiding new oncology applications. Nevertheless, major challenges remain, including isoform and function selectivity, reliable biomarkers of TG2 activity and target engagement, the consequences of sustained inhibition in normal tissues, and the design of rational combinations with chemotherapy, radiotherapy, targeted agents, and immune-checkpoint blockade. This Research Topic aims to bring together mechanistic, translational, and clinical perspectives on transglutaminases in cancer. We welcome Original Research, Reviews, Mini Reviews, Perspectives, Methods, and Brief Research Reports addressing themes including, but not limited to:o Structural and enzymatic regulation of TG isoforms in tumor cellso Non-catalytic and signaling functions of TG2 (GTP binding, scaffolding, adhesion)o Epigenetic regulation of TGM2 expression and transcriptional controlo TG2-mediated epigenetic and chromatin modifications and transcriptional reprogrammingo Transglutaminases in EMT, invasion, metastasis, and cancer stemness; extracellular matrix cross-linking, stromal stiffness, and cancer-associated fibroblastso Interactions with immune cells, immune evasion, and response to immunotherapyo Roles in therapy resistance, autophagy, redox balance, and metabolic adaptationo Tumor-suppressive and context-dependent functions of transglutaminaseso Isoform-selective inhibitors, degraders, and delivery strategieso Imaging probes, activity assays, and biomarkers for patient stratificationo Preclinical models and early clinical evidence across solid and hematological malignanciesBy assembling work that spans enzymology, tumor microenvironment biology, and drug development, this collection seeks to clarify when transglutaminases drive malignancy, when they restrain it, and how that distinction can be turned into a therapeutic strategy.Please note: Manuscripts consisting solely of bioinformatics or computational re-analysis of public metabolomic, genomic, or transcriptomic databases that are not accompanied by experimental, biological, or independent clinical validation fall outside the scope of this Research Topic. Topic editors: Nicoletta Bianchi, Salvatore Condello, Károly Dr. Jambrovics Source: https://www.frontiersin.org/research-topics/84271/transglutaminases-in-cancer-progression-mechanisms-microenvironment-and-therapeutic-opportunities