Transglutaminase 2 (TG2) is a multifunctional enzyme involved in various cellular processes, including cell survival, death, and homeostasis. It plays a critical role in the tumor microenvironment by modulating tissue remodeling and biomechanical events, influencing tumor initiation, growth, and metastasis. TG2 has diverse biological functions, such as acting as a peptide isomerase, protein kinase, and cytosolic-nuclear translocator. Its role in cancer is controversial, with evidence suggesting both oncogenic and tumor-suppressive effects, depending on the tissue and context. TG2 is involved in various cancer-related processes, including cell proliferation, apoptosis, angiogenesis, and the EMT transition. It also contributes to the formation of cancer stem cells and influences the tumor microenvironment by modulating pathways such as NF-κB, ERK1/2, and Wnt/β-catenin. TG2's expression is associated with different cancer types, with increased levels correlating with poor prognosis in melanoma, glioblastoma, pancreatic adenocarcinoma, and lung cancer. TG2's activity is regulated by various factors, including Ca²⁺ and GTP, and it can influence drug resistance and immune cell recruitment. TG2's role in cancer is complex and context-dependent, with its expression and activity varying across different tissues and cancer subtypes. Targeting TG2 may offer new therapeutic strategies for cancer treatment.Transglutaminase 2 (TG2) is a multifunctional enzyme involved in various cellular processes, including cell survival, death, and homeostasis. It plays a critical role in the tumor microenvironment by modulating tissue remodeling and biomechanical events, influencing tumor initiation, growth, and metastasis. TG2 has diverse biological functions, such as acting as a peptide isomerase, protein kinase, and cytosolic-nuclear translocator. Its role in cancer is controversial, with evidence suggesting both oncogenic and tumor-suppressive effects, depending on the tissue and context. TG2 is involved in various cancer-related processes, including cell proliferation, apoptosis, angiogenesis, and the EMT transition. It also contributes to the formation of cancer stem cells and influences the tumor microenvironment by modulating pathways such as NF-κB, ERK1/2, and Wnt/β-catenin. TG2's expression is associated with different cancer types, with increased levels correlating with poor prognosis in melanoma, glioblastoma, pancreatic adenocarcinoma, and lung cancer. TG2's activity is regulated by various factors, including Ca²⁺ and GTP, and it can influence drug resistance and immune cell recruitment. TG2's role in cancer is complex and context-dependent, with its expression and activity varying across different tissues and cancer subtypes. Targeting TG2 may offer new therapeutic strategies for cancer treatment.