Single cell eQTL Mendelian randomization prioritizes FUBP1 as a candidate therapeutic target in T cells for lung cancer

Lung cancer remains a leading cause of cancer-related mortality worldwide. Although the tumor immune microenvironment plays a critical role in disease progression, immune cell–specific causal genes and therapeutic targets remain largely undefined. We performed Mendelian randomization (MR) and colocalization analyses using single-cell expression quantitative trait loci (sc-eQTL) from 14 peripheral blood immune cell types to identify immune-related drug targets for lung cancer. Additional validations were conducted, including meta-analysis and subgroup MR analyses. DrugBank and STRING were used to evaluate predicted and curated network associations between candidate genes and established lung cancer drug targets, while single-cell RNA sequencing (scRNA-seq) expression patterns were analyzed to further prioritize candidate targets with potential therapeutic relevance. Finally, a tiered prioritization framework was applied to prioritize immune cell–associated candidate targets for lung cancer. We identified 21 putative causal genes across 13 immune cell types (43 MR associations), with 13 gene–lung cancer associations exhibiting effects in only a single immune cell type, highlighting the immune cell–specific nature of these causal relationships. Following a tiered prioritization of candidate targets, five potential high-priority targets were identified, including FUBP1 in CD4⁺ naïve and central memory T cells as a tier-1 candidate target, MPZL3 in T cells as a tier-2 target, and three additional tier-3 targets. Protein expression and immune infiltration stratification analyses further suggested an association between FUBP1 expression, CD4⁺ T-cell infiltration, and lung cancer prognosis. Finally, network analyses indicated predicted functional associations between FUBP1 and several established lung cancer drug targets, including EGFR. Our study revealed immune-mediated risk genes in lung cancer and prioritized potential drug targets, providing a framework for immune cell–based precision interventions.