Abstract
BACKGROUND: Lung cancer, particularly lung adenocarcinoma (LUAD), remains the leading cause of cancer-related deaths, with brain metastases complicating treatment and significantly reducing survival. Immune evasion is a critical factor in tumor progression, particularly in brain metastases, in which the immune microenvironment poses unique challenges to treatment. This study aimed to delineate the immune defense mechanisms that are shared between primary and brain metastatic LUAD, and to identify spatially organized programs and molecular interactions that may contribute to immune escape and therapeutic resistance. METHODS: We integrated single-cell RNA sequencing and spatial transcriptomics to investigate immune defense mechanisms shared between primary and brain metastatic LUAD tumors. Using non-negative matrix factorization (NMF) and signal distribution landscape analysis, we identified metaprogram MP1 in tumor cells, characterized by myeloid-related immunosuppressive features, significantly associated with poor prognosis. RESULTS: MP1 was significantly linked to poor prognosis and exhibited a distinct spatial enrichment at tumor borders in both primary and metastatic sites. Based on this, we propose a shared 'tumor immune defense pattern' (TIDP), which plays a central role in immune escape, tumor invasion, and intracranial colonization. We also identified ligand-receptor interactions-such as IL18RAP, CAMP (LL37), and other inflammatory or immunomodulatory molecules-that contribute to immune evasion and are upregulated in brain metastases. These may serve as biomarkers for predicting immunotherapy efficacy. MP1's functional role further suggests that targeting this program could improve therapeutic outcomes. CONCLUSIONS: This study highlights immune microenvironmental features shared between primary and metastatic tumors, particularly in the metastatic setting, and introduces TIDP as a potential framework for targeting immune evasion in brain metastases. Our findings provide a foundation for developing more targeted therapeutic strategies for patients with brain metastases from LUAD, warranting further investigation into TIDP's clinical potential.