The m6A demethylase METTL14 inhibits the development and progression of lung squamous cell carcinoma by upregulating CD19+ IgD− CD38dim

N6-methyladenosine (m6A) RNA modification plays a critical role in cancer biology, yet its causal impact on lung squamous cell carcinoma (LSCC) remains poorly understood. To address this, we intersected 19 known m6A-related genes with cis-expression quantitative trait loci datasets and identified 12 genes with reliable expression quantitative trait loci data. These genes were then used as exposures in Mendelian randomization (MR) analyses, with LSCC as the outcome. Our MR analysis revealed that methyltransferase like 14 (METTL14) exerts a significant protective effect against LSCC development (odds ratio [OR] = 0.734, 95% confidence interval [CI] = 0.567-0.950, P = .019). Further MR analysis at the immune cell level identified CD19+ IgD- CD38dim as a potential mediator. Specifically, METTL14 was positively associated with increased CD19+ IgD- CD38dim (OR = 1.636, 95% CI = 1.306-2.050, P < .001), and higher CD19 expression was associated with a reduced risk of LSCC (OR = 0.858, 95% CI = 0.767-0.961, P = .008). Mediation analysis indicated CD19+ IgD- CD38dim accounted for ~24.3% of the total effect of METTL14 on LSCC risk. Altogether, these findings suggest that the m6A demethylase METTL14 plays a protective role in the pathogenesis of LSCC, potentially by upregulating CD19+ IgD- CD38dim. This study is the first to establish a causal link between an m6A demethylase and LSCC risk, highlighting a novel METTL14-CD19-LSCC regulatory axis. The results not only provide new mechanistic insights into LSCC pathogenesis but also suggest potential clinical implications, including the development of METTL14-related biomarkers and immune-based therapeutic strategies.