The study introduces LOHHLA, a computational tool for estimating allele-specific HLA copy number from sequencing data, which reveals that HLA loss occurs in 40% of early-stage non-small-cell lung cancers (NSCLCs). HLA loss is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA loss alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggest that HLA loss is an immune escape mechanism subject to strong microenvironmental selection pressures. LOHHLA refines neoantigen prediction and may have implications for understanding resistance mechanisms and immunotherapeutic approaches targeting neoantigens.The study introduces LOHHLA, a computational tool for estimating allele-specific HLA copy number from sequencing data, which reveals that HLA loss occurs in 40% of early-stage non-small-cell lung cancers (NSCLCs). HLA loss is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA loss alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggest that HLA loss is an immune escape mechanism subject to strong microenvironmental selection pressures. LOHHLA refines neoantigen prediction and may have implications for understanding resistance mechanisms and immunotherapeutic approaches targeting neoantigens.