IL-1β-associated NNT acetylation orchestrates iron-sulfur cluster maintenance and cancer immunotherapy resistance

Mol Cell. 2023 Jun 1;83(11):1887-1902.e8. doi: 10.1016/j.molcel.2023.05.011. Epub 2023 May 26.


Interleukin-1β (IL-1β) is a key protein in inflammation and contributes to tumor progression. However, the role of IL-1β in cancer is ambiguous or even contradictory. Here, we found that upon IL-1β stimulation, nicotinamide nucleotide transhydrogenase (NNT) in cancer cells is acetylated at lysine (K) 1042 (NNT K1042ac) and thereby induces the mitochondrial translocation of p300/CBP-associated factor (PCAF). This acetylation enhances NNT activity by increasing the binding affinity of NNT for NADP+ and therefore boosts NADPH production, which subsequently sustains sufficient iron-sulfur cluster maintenance and protects tumor cells from ferroptosis. Abrogating NNT K1042ac dramatically attenuates IL-1β-promoted tumor immune evasion and synergizes with PD-1 blockade. In addition, NNT K1042ac is associated with IL-1β expression and the prognosis of human gastric cancer. Our findings demonstrate a mechanism of IL-1β-promoted tumor immune evasion, implicating the therapeutic potential of disrupting the link between IL-1β and tumor cells by inhibiting NNT acetylation.

Keywords: NNT; acetylation; ferroptosis; immunotherapy; interleukin-1β.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Humans
  • Immunotherapy
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • NADP Transhydrogenases* / genetics
  • NADP Transhydrogenases* / metabolism
  • Neoplasms* / drug therapy
  • Neoplasms* / genetics
  • Protein Processing, Post-Translational


  • NADP Transhydrogenases
  • Interleukin-1beta