Genetic Intratumor Heterogeneity Remodels the Immune Microenvironment and Induces Immune Evasion in Brain Metastasis of Lung Cancer

Introduction: Brain metastasis, with the highest incidence in patients with lung cancer, significantly worsens prognosis and poses challenges to clinical management. To date, how brain metastasis evades immune elimination remains unknown. Methods: Whole-exome sequencing and RNA sequencing were performed on 30 matched brain metastasis, primary lung adenocarcinoma, and normal tissues. Data from The Cancer Genome Atlas primary lung adenocarcinoma cohort, including multiplex immunofluorescence, were used to support the findings of bioinformatics analysis. Results: Our study highlights the key role of intratumor heterogeneity of genomic alterations in the metastasis process, mainly caused by homologous recombination deficiency or other somatic copy number alteration–associated mutation mechanisms, leading to increased genomic instability and genomic complexity. We further proposed a selection model of brain metastatic evolution in which intratumor heterogeneity drives immune remodeling, leading to immune escape through different mechanisms under local immune pressure. Conclusions: Our findings provide novel insights into the metastatic process and immune escape mechanisms of brain metastasis and pave the way for precise immunotherapeutic strategies for patients with lung cancer with brain metastasis.