Background <p>Cytochrome P450 oxidoreductase (POR) plays a vital role in ferroptosis within lung cancer. A potential link exists between ferroptosis-related genes and immune cell activity. This research aimed to confirm whether POR influences lung cancer by modulating immune cells.</p> Methods <p>Genetic variants of the POR gene were identified from lung tissue expression quantitative trait loci (eQTL) data using single nucleotide polymorphisms (SNPs). A genome-wide study of 40,187 Europeans found variants linked to lung cancer. Mediation analysis on 731 immunophenotypes was done to assess their mediating effect on the POR gene-lung cancer relationship.</p> Results <p>This study identified four SNPs for further investigation. Mediation analysis suggested that three immune cell traits might mediate the effect of POR on lung cancer, with CD11c on granulocyte showing a clear mediation effect (<i>β</i>₁₂ = −&#xa0;0.01, mediation proportion = 8.18%). There was a negative correlation between CD11c on granulocyte and the POR gene (<i>β</i>₁ = −&#xa0;0.23), as well as a positive correlation between CD11c on granulocyte and lung cancer risk (<i>β</i>₂ = 0.05).</p> Conclusions <p>Our analysis revealed that increased expression in the POR gene was linked to a lower genetically predicted risk of lung cancer, with a significant mediation effect by the CD11c on granulocyte.</p>