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

ABSTRACT: 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. Importantly, blockade of CD73 sensitized UBD‑overexpressed cancer cells to anti-PD‑1 immunotherapy by restoring intratumor CD8+ T cell function. We have thus revealed a previously unrecognized mechanism for CRC resistance to anti‑PD‑1 therapy through UBD‑CD73‑adenosine mediated suppression of CD8+ T cells. This new information potentially provides a novel strategy to overcome resistance to PD‑1 blockade in patients with CRC.

ORGANISM(S): Mus musculus

PROVIDER: GSE233462 | GEO | 2026/05/23

REPOSITORIES: GEO