Lung adenocarcinoma exhibits high incidence and mortality rates, presenting a significant health concern. Concurrently, the COVID-19 pandemic has emerged as a grave global public health challenge. Existing literature suggests that T cells, pivotal components of cellular immunity, are integral to both antiviral and antitumor responses. Yet, the nuanced alterations and consequent functions of T cells across diverse disease states have not been comprehensively elucidated. We gathered transcriptomic data of peripheral blood mononuclear cells from lung adenocarcinoma patients, COVID-19 patients, and healthy controls. We followed a standardized analytical approach for quality assurance, batch effect adjustments, and preliminary data processing. We discerned distinct T cell subsets and conducted differential gene expression analysis. Potential key genes and pathways were inferred from GO and Pathway enrichment analyses. Additionally, we implemented Mendelian randomization to probe the potential links between pivotal genes and lung adenocarcinoma susceptibility. Our findings underscored a notable reduction in mature CD8 + central memory T cells in both lung adenocarcinoma and COVID-19 cohorts relative to the control group. Notably, the downregulation of specific genes, such as TRGV9, could impede the immunological efficacy of CD8 + T cells. Comprehensive multi-omics assessment highlighted genetic aberrations in genes, including TRGV9, correlating with heightened lung adenocarcinoma risk. Through rigorous single-cell transcriptomic analyses, this investigation meticulously delineated variations in T cell subsets across different pathological states and extrapolated key regulatory genes via an integrated multi-omics approach, establishing a robust groundwork for future functional inquiries. This study furnishes valuable perspectives into the etiology of multifaceted diseases and augments the progression of precision medicine.© 2024. The Author(s).