m6A-modified circZNF548 regulates exosomal miR-7108-3p to activate CD3+CD8+ T cells and suppress NSCLC growth by JMY.

Abstract

Background: Communication between cancer cells and tumor microenvironment (TME) plays a complicated role in cancer malignancy. Circular RNAs (circRNAs), known for their stability and conservation, contribute to TME remodeling in various cancers. This study aims to investigate the role of N6-methyladenosine (m6A)-modified circZNF548 in the proliferation and migration of non-small cell lung cancer (NSCLC) within the TME.

Results: circZNF548 expression is lower in NSCLC tissues than that in adjacent normal controls, and the higher circZNF548 levels correlate with the improved patient survival. circZNF548 overexpression suppresses NSCLC cell proliferation and migration, whereas siRNA-mediated downregulation promotes proliferation and migration. METTL14 overexpression decreases circZNF548 levels through m6A modification, whereas siRNA-mediated METTL14 downregulation increases them. circZNF548 interacts with and regulates the abundance of exosomal miR-7108-3p. CD8A and junction-mediating and regulating Y protein (JMY) are identified as downstream targets of miR-7108-3p. Exosomal miR-7108-3p suppresses the activation of CD3⁺CD8⁺ T cells by decreasing CD107a levels and downregulating the production of IFN-γ, perforin 1, and granzyme B in TME. circZNF548 promotes CD3 + CD8 + T cell-mediated cytotoxicity and inhibits NSCLC cell proliferation by modulating exosomal miR-7108-3p and the JMY-p53 pathway.

Conclusions: m6A-modified circZNF548 suppresses NSCLC cell proliferation and migration by enhancing anti-tumor immunity via exosomal miR-7108-3p and the JMY-p53 pathway. These findings suggest new therapeutic targets for NSCLC.