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J Cancer 2024; 15(2):560-576. doi:10.7150/jca.90059 This issue Cite

Review

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

Tingting Li^1,2, Zhe Lei³, Lin Wei², Kai Yang¹, Jinhong Shen^4✉, Lin Hu^1✉

1. State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X) and Collaborative Innovation Centre of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, 199 Renai Road, Suzhou 215123, China.
2. Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China.
3. Department of Pathology, The First Affiliated Hospital of Soochow University, Suzhou 215006 Jiangsu, China.
4. Shanghai Key Laboratory of Sleep Disordered Breathing, Department of Otolaryngology-Head and Neck Surgery, Otolaryngology Institute of Shanghai Jiaotong University, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200233, China.

✉ Corresponding authors: Lin Hu (hulinedu.cn), Jinhong Shen (sjh_hello2020com).

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.

Keywords: TRAF6, Inflammatory, Tumor microenvironment, Tumor immunotherapy, Therapeutic target

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