Abstract

Background and Purpose IGF2BP1 stabilizes oncogenic mRNAs via m6A binding to drive lung adenocarcinoma (LUAD) progression, yet how this modification orchestrates immune evasion remains unclear. Experimental Approach Bioinformatics, RT-qPCR and Western Blotting (WB) first profiled IGF2BP1 expression in LUAD. RNA pull-down, IL-11 stability assays, ELISA and confocal imaging screened and validated IGF2BP1/IL-11 as the key oncogenic axis. ELISA, cytotoxicity experiments and flow cytometry were applied in the exploration of the function of the IGF2BP1/IL-11 axis in LUAD. Bioinformatics analysis, IGF2BP1 half-life detection, WB and ubiquitination experiments were employed to identify the interaction between KCTD10 and IGF2BP1. Allograft experiments were conducted to validate the impact of the KCTD10/IGF2BP1/IL-11 axis on tumour immune escape. Clinical correlation analysis was based on samples of LUAD patients before and after PD-1/PD-L1 inhibitor treatment. Key Results IGF2BP1 was up-regulated in LUAD, exhibiting an association with adverse prognosis. Mechanistically, we observed that IGF2BP1 stabilized IL-11 mRNA in an N6-methyladenosine (m6A)-dependent manner, leading to higher protein expression of IL-11, thereby dampening the cytotoxicity and proliferation of CD8 + cells as well as the expression of TNF-α, IFN-γ and IL-2. Furthermore, KCTD10 overexpression facilitated ubiquitination and degradation of IGF2BP1, and its combination with an anti-IL-11 monoclonal antibody dramatically enhanced therapeutic efficacy. Conclusion and Implications These findings reveal that KCTD10 degrades IGF2BP1 by ubiquitination, regulates m6A modification of IL-11, and restrains immune evasion in LUAD. Our study identifies potential targets for immunotherapy and proffers new therapeutic options for LUAD patients.