Nedd8, a ubiquitin-like protein, plays a crucial role in eukaryotic cell biology. It is involved in the regulation of cullin-RING E3 ligase (CRL)-catalysed protein ubiquitylation. Neddylation, the process of attaching Nedd8 to substrate proteins, is a key post-translational modification in diverse biological pathways [1,3].

Genetic deletion of Nedd8 in cancer cells, as shown in triple-negative breast cancer (TNBC) models, causes a vulnerability to nivolumab (anti-PD-1). Although initial cell division is delayed, cell proliferation recovers. Nedd8-deficient cells exhibit enhanced immunogenicity, and in female immunocompetent mice, PD-1 blockade leads to CD8+ T-cell-mediated tumor regression in Nedd8-deficient EO771 tumors [2].

In conclusion, Nedd8 is essential for regulating CRL-mediated protein ubiquitylation. Its loss in cancer cells, especially in TNBC, reveals a potential for synergistic treatment with immune checkpoint blockade therapies. Understanding Nedd8's function through gene-knockout models provides insights into its role in disease and potential therapeutic strategies.