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Cancer-Intrinsic Protein Neddylation Modulates the Intratumoral Immune Landscape to Constrain Immune Checkpoint

Irineos Papakyriacou1,2, Yonglin Lu1,2, Malin Jarvius3,4

  • 1Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

Cancer Immunology Research
|June 22, 2026
PubMed

Insights

Protein neddylation in cancer cells hinders immune response to checkpoint blockade. Inhibiting neddylation or using specific compounds enhances anti-tumor immunity and improves immunotherapy outcomes.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • The precise mechanisms governing response to immune checkpoint blockade (ICB) therapy are not fully understood.
  • Identifying intrinsic cancer networks that influence ICB efficacy is crucial for improving treatment outcomes.

Purpose of the Study:

  • To investigate the role of protein neddylation in regulating anti-tumor immunity and response to ICB therapy.
  • To explore potential therapeutic strategies targeting protein neddylation to enhance immunotherapy.

Main Methods:

  • Analysis of single-cell RNA sequencing (scRNA-seq) data from breast cancer patients.
  • Genetic ablation of protein neddylation in murine tumor models.
  • scRNA-seq and spatial transcriptomics of neddylation-deficient tumors.
  • High-content phenotypic screening of compounds affecting protein neddylation.

Main Results:

  • Pre-therapy NEDD8 mRNA expression in cancer cells negatively correlated with T-cell expansion during pembrolizumab treatment.
  • Genetic elimination of protein neddylation in mouse tumors led to curative responses to PD-1/PD-L1 blockade.
  • Neddylation deficiency altered spatial immune cell distribution and signatures.
  • Lipid inhibitors and ferroptosis inducers required protein neddylation for phenotypic changes in cancer cells and enhanced PD-1 blockade efficacy.

Conclusions:

  • Protein neddylation plays a significant role in suppressing anti-tumor immunity.
  • Targeting protein neddylation presents a promising therapeutic avenue to enhance the effectiveness of immune checkpoint blockade therapy.
  • Compounds modulating neddylation can improve immunotherapy outcomes and protect against tumor recurrence.

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