The STUB1 gene (STIP1 homology and U-box-containing protein 1), located at 16q13.3, encodes the CHIP (carboxyl terminus of Hsc70-interacting protein), an essential E3 ligase involved in protein quality control. CHIP comprises three domains: an N-terminal tetratricopeptide repeat (TPR) domain, a middle coiled-coil domain, and a C-terminal U-box domain. It functions as a co-chaperone for heat shock protein (HSP) via the TPR domain and as an E3 ligase, ubiquitinating substrates through its U-box domain. Numerous studies suggest that STUB1 plays a crucial role in various physiological process, such as aging, autophagy, and bone remodeling. Moreover, emerging evidence has shown that STUB1 can degrade oncoproteins to exert tumor-suppressive functions, and it has recently emerged as a novel player in tumor immunity. This review provides a comprehensive overview of STUB1’s role in cancer, including its clinical significance, impact on tumor progression, dual roles, tumor stem cell-like properties, angiogenesis, drug resistance, and DNA repair. In addition, we explore STUB1’s functions in immune cell differentiation and maturation, inflammation, autoimmunity, antiviral immune response, and tumor immunity. Collectively, STUB1 represents a promising and valuable therapeutic target in cancer and immunology.