IL-23 promotes PD-L1 expression and tumor immune evasion via METTL16 pathway.
TL;DR
It is elucidated that IL-23 upregulates METTL16, which in turn enhances PD-L1 expression and facilitates tumor immune escape, which establishes the IL-23/METTL16/PD-L1 axis as a novel regulatory pathway and potential therapeutic target in cancer immunotherapy.
Abstract
Interleukin-23 (IL-23) is a pivotal cytokine implicated in tumor progression and immune evasion, yet its precise molecular mechanisms remain incompletely characterized. In this study, we elucidate that IL-23 upregulates METTL16, which in turn enhances PD-L1 expression and facilitates tumor immune escape. Integrated analysis of TCGA and GEO datasets revealed the co-upregulation of IL-23 and METTL16 in lung and colon carcinomas, both of which are correlated with poor clinical outcomes. Mechanistically, IL-23 induces METTL16 expression in cancer cells via JAK-STAT3 pathway-mediated transcriptional activation. Notably, METTL16 augments PD-L1 levels via an m6A-independent mechanism by directly binding to PD-L1 and impeding its SPOP-mediated ubiquitination and proteasomal degradation. In vivo, METTL16 promotes colon cancer xenograft growth while concurrently suppressing CD8+ T cell infiltration and IFN-γ secretion within the tumor microenvironment. Collectively, these findings establish the IL-23/METTL16/PD-L1 axis as a novel regulatory pathway and potential therapeutic target in cancer immunotherapy.