Ubiquitin D drives colorectal cancer immune evasion and resistance to anti PD1 immunotherapy

Ubiquitin D drives colorectal cancer immune evasion and resistance to anti PD1 immunotherapy by suppressing FBXW7 mediaUbiquitin D drives colorectal cancer immune evasion and resistance to anti PD1 immunotherapy by suppressing FBXW7 mediated CD73 degradation [scRNA-seq] The majority of patients with colorectal cancer (CRC) can’t benefit from anti-PD-1 immunotherapy due to an insufficient T cell response in the tumor microenvironment (TME); however, the underlying mechanism remains unknown.

Here, we show that ubiquitin D (UBD) in tumor cells inhibits CD8+ T cell‑mediated anti‑tumor responses, and consequently mediates resistance to anti‑PD‑1 immunotherapy in experimental and clinical CRC. Mechanistically, UBD disrupted E3 ligase F‑box and WD repeat domain‑containing 7 (FBXW7)‑induced proteasome degradation of CD73, thereby increasing the concentration of intracellular adenosine, which subsequently suppressed CD8+ T cell function in the TME.