A comprehensive pan-cancer analysis identifies AP1S1 as a novel biomarker for predicting prognosis and immunotherapy response

AP1S1 has lately emerged as a cancer-associated gene, though existing research offers restricted insight. This study sought to elucidate its roles and regulatory pathways throughout pan-cancer. Pan-cancer bulk sequencing data and online web platforms were utilized to investigate the associations of AP1S1 with survival outcomes, genomic instability, cancer stem cell properties, DNA repair mechanisms, and immune infiltrates. Additionally, the connection between AP1S1 level and immune cell populations was confirmed through single-cell datasets and the SpatialDB database. We employed the cMap web tool to identify compounds targeting AP1S1 and utilized PDB along with Autodock Vina for 3D modeling and molecular docking of AP1S1. AP1S1 is significantly dysregulated across various cancer types, providing notable diagnostic and prognostic value in the majority of cases studied. Notably, patients with BRCA, KICH, GBM, ACC, CESC, and UVM expressing elevated AP1S1 levels demonstrate decreased survival duration and diminished immunotherapy efficacy. AP1S1 expression levels were associated with genomic instability, methylation, DNA repair, stemness, and TME scores across various cancer types. Additionally, a positive relationship emerged between the immune checkpoint CD276 and AP1S1. We confirmed AP1S1 as a marker for M2 macrophages and demonstrated its association with other immune cells. Elevated AP1S1 levels correlate with reduced M2 macrophage infiltration, increased M1 macrophage and Treg infiltration, and show a negative association with antigen-presenting and various immune inhibitory molecules. Finally, we identify SU11652 as a candidate inhibitor targeting AP1S1-driven oncogenic activities. Our study underscores AP1S1 expression as a promising biomarker linked to DNA repair, useful for predicting prognosis and immunotherapy effectiveness in various human cancers, and indicates its significance for innovative antitumor drug development or enhancing immunotherapy.