The Role of TRAF6 in Cancer: From Molecular Mechanisms to Therapeutic Strategies.

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an E3 ubiquitin ligase that plays a crucial role in inflammation, immune responses, and tumor development. It was reported that TRAF6 primarily catalyzes K63-linked polyubiquitination to stabilize substrate proteins, thereby facilitating the malignant phenotype of tumors. Beyond its cytoplasmic roles, TRAF6 undergoes nuclear translocation in response to specific stimuli, where it interacts with chromatin modifiers. TRAF6 acts as a central mediator in key signaling pathways downstream of the Toll-like receptor, interleukin-1 receptor, and tumor necrosis factor receptor superfamilies, including NF-κB activation. TRAF6 exerts diverse oncogenic functions, including promoting cell proliferation, migration, metastasis, immune evasion, and therapy resistance. This involves modulating cellular pathways such as NF-κB and MAPK signaling, which contribute to malignant progression. Aberrant TRAF6 activation contributes to the pathogenesis of multiple malignancies, including colorectal cancer, melanoma, hepatocellular carcinoma, and acute myeloid leukemia, making it a promising therapeutic target for cancer treatment. This review summarizes the structural features, substrate diversity, and multifaceted roles of TRAF6 in cancer, as well as the development of TRAF6-targeting drugs and strategies. We hope this review can provide a comprehensive perspective on TRAF6-targeted therapeutic strategies for cancer.