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

Mengna Xu1,2, Weixiao Liu1,2, Fan Liu1,2

  • 1Department of Cell Biology, Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069 China.

Phenomics (Cham, Switzerland)
|June 4, 2026
PubMed

Insights

Protein neddylation, a key cellular process, impacts tumor development and resistance to anti-cancer drugs like MLN4924. Targeting neddylation may enhance cancer immunotherapy effectiveness.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Protein neddylation involves the conjugation of NEDD8 (neural precursor cell expressed developmentally downregulated protein 8) to substrates via an enzymatic cascade.
  • Neddylation regulates Cullin-RING ligases (CRLs), crucial for protein degradation, thereby influencing numerous biological functions, including tumor progression.
  • MLN4924, a NEDD8-activating enzyme (NAE) inhibitor, shows anti-cancer potential but faces challenges due to acquired resistance.

Purpose of the Study:

  • To review the organization of protein neddylation.
  • To explore the modulatory roles of neddylation in tumor cells and the tumor immune microenvironment (TIME).
  • To discuss the implications of neddylation in MLN4924 resistance and its potential combination with immunotherapies.

Main Methods:

  • Literature review on protein neddylation pathways.
  • Analysis of neddylation's impact on tumor cell biology.
  • Investigation of neddylation's influence on the tumor immune microenvironment (TIME).

Main Results:

  • Neddylation directly and indirectly modulates the tumor immune microenvironment (TIME).
  • Understanding neddylation's role provides insights into MLN4924 resistance mechanisms.
  • Neddylation impacts both tumor cells and immune cells within the tumor context.

Conclusions:

  • Targeting neddylation presents a promising strategy for cancer therapy.
  • Combining neddylation inhibitors with immunotherapies may overcome resistance and improve treatment efficacy.
  • Further research into neddylation's intricate roles could unlock novel therapeutic avenues.
Keywords:
AnticancerImmunityMLN4924Protein neddylation

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