Protein Neddylation Beyond Tumor Cells is a Vital Modulator of Anticancer Immunity.

Abstract

Protein neddylation modification involves transfer of neural precursor cell expressed developmentally downregulated protein 8 (NEDD8), a ubiquitin-like protein, to substrates through a three-step enzymatic cascade mediated by NEDD8-activating enzyme (NAE), conjugating enzyme and ligases. Given Cullin-RING ligases (CRLs) as the uppermost substrates which regulate degradation of numerous proteins, neddylation modulates numerous biological functions, including tumor development. MLN4924, a potent NAE inhibitor, has emerged as a promising anti-cancer agent based on neddylation interference. However, resistance to MLN4924 poses a significant challenge. Growing evidence suggests that neddylation directly and indirectly modulates the tumor immune microenvironment (TIME), providing novel insights into its impact on tumor dynamics and the development of resistance to MLN4924. This understanding indicates that targeting neddylation could potentially be combined with immunotherapies for more effective treatment strategies. Here, we briefly outline how neddylation is organized and its modulatory roles in both tumor cells and intertumoral immune cells, proposing an optimistic outlook for neddylation-targeted therapy.