This study investigates the immunogenetic basis for lung cancer risk, leveraging data from the UK Biobank and FinnGen. The research finds that heterozygosity at the human leukocyte antigen (HLA)-II loci is associated with reduced lung cancer risk in smokers. Fine-mapping of the peptide binding groove implicated amino acid heterozygosity in reducing lung cancer risk. Single-cell RNA sequencing revealed that smoking drives upregulation of HLA-II and pro-inflammatory pathways in alveolar macrophages. Additionally, widespread loss of HLA-II heterozygosity (LOH) in lung cancer tumors favored the loss of alleles with larger neopeptide repertoires. These findings highlight the importance of genetic variation in immunosurveillance as a critical risk factor for lung cancer.This study investigates the immunogenetic basis for lung cancer risk, leveraging data from the UK Biobank and FinnGen. The research finds that heterozygosity at the human leukocyte antigen (HLA)-II loci is associated with reduced lung cancer risk in smokers. Fine-mapping of the peptide binding groove implicated amino acid heterozygosity in reducing lung cancer risk. Single-cell RNA sequencing revealed that smoking drives upregulation of HLA-II and pro-inflammatory pathways in alveolar macrophages. Additionally, widespread loss of HLA-II heterozygosity (LOH) in lung cancer tumors favored the loss of alleles with larger neopeptide repertoires. These findings highlight the importance of genetic variation in immunosurveillance as a critical risk factor for lung cancer.