A Pan‐Cancer Atlas of TIPE2 Identifies Its Association With the Tumor Immune Microenvironment, Prognosis, and Immunotherapeutic Potential

The tumor microenvironment (TME) plays a pivotal role in tumorigenesis, progression, and metastasis. Tumor necrosis factor alpha-induced protein 8-like 2 (TNFAIP8L2; TIPE2), a member of the TIPE family, is a key regulator of immune homeostasis. In this study, we comprehensively characterized the pan-cancer landscape of TIPE2 and evaluated its potential significance for prognosis and immunotherapy-related stratification. Using multiomics data from public databases such as TCGA, GTEx, and HPA, we systematically analyzed TIPE2 expression patterns, genetic and epigenetic alterations, and their associations with clinical outcomes and immune characteristics across 33 cancer types. TIPE2 was found to be enriched in immune cells and frequently dysregulated in tumors compared with normal tissues. TIPE2 expression demonstrated a significant correlation with the infiltration of various immune cell populations across most cancers and exhibited strong associations with the expression of immune checkpoint genes. Alterations in TIPE2, along with aberrant methylation, were identified in a subset of tumors, indicating multilayered regulatory mechanisms. Gene set enrichment analysis further demonstrated that elevated TIPE2 expression is associated with immune-related pathways. Survival analyses demonstrated that TIPE2 expression was associated with overall survival and disease-free survival across multiple cancer types, exhibiting directionally heterogeneous effects depending on tumor context. Collectively, these findings identify TIPE2 as an immune-relevant biomarker candidate with prognostic significance across various cancers and warrant further mechanistic and clinical validation to elucidate its potential role in immunotherapy-based patient stratification.