Tumor Necrosis Factor Receptor-Associated Factor 6 and Human Cancer: A Systematic Review of Mechanistic Insights, Functional Roles, and Therapeutic Potential.

ABSTRACT

Cancer imposes a substantial burden and its incidence is persistently increasing in recent years. Cancer treatment has been difficult due to its inherently complex nature. The tumor microenvironment (TME) includes a complex interplay of cellular and noncellular constituents surrounding neoplastic cells, intricately contributing to the tumor initiation and progression. This critical aspect of tumors involves a complex interplay among cancer, stromal, and inflammatory cells, forming an inflammatory TME that promotes tumorigenesis across all stages. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is implicated in modulating various critical processes linked to tumor pathogenesis, including but not limited to the regulation of tumor cell proliferation, invasion, migration, and survival. Furthermore, TRAF6 prominently contributes to various immune and inflammatory pathways. The TRAF6-mediated activation of nuclear factor (NF)-κB in immune cells governs the production of proinflammatory cytokines. These cytokines sustain inflammation and stimulate tumor growth by activating NF-κB in tumor cells. In this review, we discuss various types of tumors, including gastrointestinal cancers, urogenital cancers, breast cancer, lung cancer, head and neck squamous cell carcinoma, uterine fibroids, and glioma. Employing a rigorous and systematic approach, we comprehensively evaluate the functional repertoire and potential roles of TRAF6 in various cancer types, thus highlighting TRAF6 as a compelling and emerging therapeutic target worthy of further investigation and development.