Shi C, Wang Y, Wu M, Chen Y, Liu F, Shen Z, Wang Y, Xie S, Shen Y, Sang L, Zhang Z, Gao Z, Yang L, Qu L, Yang Z, He X, Guo Y, Pan C, Che J, Ju H, Liu J, Cai Z, Yan Q, Yu L, Wang L, Dong X, Xu P, Shao J, Liu Y, Li X, Wang W, Zhou R, Zhou T, Lin A

Immune checkpoint blockade therapies targeting the PD-L1/PD-1 axis have demonstrated clear clinical benefits. Improved understanding of the underlying regulatory mechanisms might contribute new insights into immunotherapy. Here, we identify transmembrane and ubiquitin-like domain-containing protein 1 (TMUB1) as a modulator of PD-L1 post-translational modifications in tumor cells. Mechanistically, TMUB1 competes with ...

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HECT, UBA and WWE domain-containing protein 1 (HUWE1), a E3 ubiquitin ligase, to interact with PD-L1 and inhibit its polyubiquitination at K281 in the endoplasmic reticulum. Moreover, TMUB1 enhances PD-L1 N-glycosylation and stability by recruiting STT3A, thereby promoting PD-L1 maturation and tumor immune evasion. TMUB1 protein levels correlate with PD-L1 expression in human tumor tissue, with high expression being associated with poor patient survival rates. A synthetic peptide engineered to compete with TMUB1 significantly promotes antitumor immunity and suppresses tumor growth in mice. These findings identify TMUB1 as a promising immunotherapeutic target.

Date: Nov. 14, 2022

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