WTAP-mediated m6A methylation of CEP55 promotes immune evasion in lung adenocarcinoma by activating the PI3K/AKT/mTOR pathway
摘要
Lung adenocarcinoma (LUAD) is the most lethal subtype of lung cancer, and its occurrence and progression are closely correlated with immune escape. CEP55 is upregulated in a variety of malignancies and participates in tumor progression, yet its specific role in the immune regulation of LUAD remains poorly defined. Due to the unclear mechanism of immune escape, the therapeutic efficacy of immunotherapy for LUAD is still unsatisfactory. Therefore, it is essential to further elucidate the underlying molecular mechanisms and identify novel therapeutic targets. This study aims to explore the biological function of CEP55 in LUAD immune escape, as well as to clarify its upstream regulatory mechanism and downstream signaling pathways. CEP55 expression in LUAD tissues was assessed utilizing data from TCGA-LUAD and validated in cells. Bioinformatics approaches were employed to explore CEP55-enriched signaling pathways and their link to CD8⁺ T cell infiltration. A CD8⁺ T-tumor cell co-cultured model was established, and LDH release, ELISA, and CFSE staining were utilized to assess CD8⁺ T cell cytotoxicity and proliferation. To uncover the role of CEP55 in LUAD cell behavior, we employed CCK-8, EdU labeling, Transwell assays, and flow cytometry to systematically evaluate its effects on proliferation, migration, invasion, and apoptosis. Western blotting was performed to measure key signaling pathway proteins expression level. Potential upstream regulators of CEP55 m6A modification were identified through database mining, followed by validation using RIP, MeRIP-qPCR, and WB. CEP55 was highly expressed in LUAD and inversely associated with CD8⁺ T cell infiltration. Knockdown of CEP55 in LUAD enhanced tumor-killing activity of CD8⁺ T cells in a co-culture system and significantly suppressed LUAD cell proliferation, migration, invasion, and anti-apoptotic capacity. CEP55 was positively correlated with WTAP in LUAD. WTAP stabilized CEP55 mRNA expression via m6A modification, while CEP55 activated the PI3K/AKT/mTOR pathway, upregulating PD-L1. This led to CD8⁺ T cell exhaustion and promoted tumor immune evasion. This study reveals a critical mechanism whereby WTAP upregulates CEP55 expression via m⁶A modification, thereby activating the PI3K/AKT/mTOR signaling pathway, inhibiting the anti-tumor activity of CD8⁺ T cells, and ultimately facilitating LUAD progression. These findings indicate that CEP55 serves as a promising therapeutic target for LUAD immunotherapy, providing novel theoretical evidence to improve the efficacy of immune treatment.