<scp>UBE</scp> 2 <scp>C</scp> ‐Mediated <scp>CD</scp> 147‐ <scp>CTLA</scp> ‐4 Axis Promotes T Cell Exhaustion and Immunosuppressive Microenvironment in Bladder Cancer

ABSTRACT Despite immune checkpoint inhibitors (ICIs) having benefited bladder cancer (BCa) patients, their limited response rates urge elucidation of intrinsic resistance mechanisms. In this study, we demonstrated that ubiquitin conjugating enzyme E2C (UBE2C) promotes the proliferation, invasion, and migration of BCa and inhibits DNA damage, accompanied by a decrease in T cell abundance. In syngeneic C57BL/6 BCa models and BCa–CD8 + T‐cell cocultures, UBE2C silencing reduced CD147 and CTLA‐4 abundance, restored IFN‐γ, TNF‐α, and TGF‐β secretion, expanded CD3 + CD8 + subsets, and attenuated tumor growth, invasion, and migration. Conversely, UBE2C or CD147/CTLA‐4 overexpression reinstated T‐cell exhaustion and malignant progression. Targeting the UBE2C–CD147–CTLA‐4 axis resensitizes BCa to immune attack, offering a rational strategy to extend the efficacy of current immunotherapies.