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

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.