Background: Transgelin-2 (TAGLN2) has long been regarded as an actin-binding protein that modulates actin gelation and controls actin cytoskeleton dynamics. However, recent studies have reported that TAGLN2 can directly or indirectly participate in multiple cancer-related processes, including cell migration, proliferation, differentiation, and apoptosis. To further investigate the role of TAGLN2 in carcinogenesis, a comprehensive analysis was launched to evaluate the expression status and prognostic value of TAGLN2 in pan-cancer. Methods: Herein, data was retrieved from publicly online websites and databases, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE), UCSC Xena, cBioPortal, Human Protein Atlas (HPA), TIMER2.0, CancerSEA, GDSC, and ImmuCellAI. Gene expression pattern and its correlation with prognosis were assessed across cancer types. Moreover, an analysis was conducted to explore the relationships between TAGLN2 and methylation, copy number values (CNVs), tumor microenvironment (TME), immune cell infiltration, immune-relevance genes, tumor mutation burden (TMB), microsatellite instability (MSI), and IC50. Additionally, R package "clusterProfiler" was utilized to perform enrichment analysis on TAGLN2. Finally, the ability of TAGLN2 as an oncogene was preliminarily verified in vitro in UCEC. Results: Our findings revealed that TAGLN2 was specifically overexpressed and related to an unfavorable prognosis in most cancers. There was a significant connection between TAGLN2 expression and methylation and CNVs. Besides, we identified TAGLN2 correlated to TME, immune cell infiltration, immune-relevant genes, TMB, and MSI, suggesting an immunoregulatory role in cancers. Notably, TAGLN2 expression showed a positive correlation with macrophages, and cancer-associated fibroblasts, whereas a negative correlation with the infiltration degree of B cells. Mechanically, the results obtained from Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) provided theory-supportive evidence that TAGLN2 interlinkages with immunity and programmed cell death. Overall, anti-tumor drugs were overtly associated with TAGLN2 dysregulation among diverse cancers. At last, UCEC cell lines with TAGLN2-depleting had an inhibition of the migration and invasion ability. Conclusions: These findings enriched the knowledge about the role of TAGLN2 in tumorigenesis and progression, revealing TAGLN2 may serve as a potential therapeutic strategy for various malignancies.© The author(s).