Fig. 7: Schematic summary of the regulation of STING stability by ISGylation and its implications in lung cancer immunotherapy.
From: ISGylation prevents autophagic degradation of STING and promotes antitumor immunity in lung cancer
ISGylation at key lysine residues (K236, K338, K347, and K370) on STING prevents its autophagic degradation by disrupting interactions with p62 and LC3, thereby maintaining STING protein stability and enhancing type I interferon (IFN-I) production. USP18, a deISGylating enzyme, is overexpressed in lung cancer and negatively correlates with STING protein levels, promoting tumor progression by reducing STING ISGylation. Tanshinone IIA sulfonate (TST), a novel USP18 inhibitor, promotes STING ISGylation and stability, leading to increased IFN-I production and enhanced antitumor immunity. Combined treatment with TST and STING agonist diABZi synergistically strengthens antitumor immune responses and inhibits lung tumor growth in mouse models, offering a potential therapeutic strategy for lung cancer patients with low STING expression.
