Identification of altered immune landscape at single-cell resolution in NSCLC brain metastasis and its association with poor immune checkpoint inhibitor responses.

Brain metastasis, a common complication of advanced non-small cell lung cancer (NSCLC), leads to poor prognosis and reduces the efficacy of immune checkpoint inhibitors (ICIs). However, the mechanisms underlying this diminished ICI response remain unclear. Here we perform single-cell RNA sequencing on 101,959 tumor-infiltrating immune cells from primary tumors and brain metastases to delineate their distinct immune landscapes. Brain metastases display profound immunosuppressive reprogramming, characterized by enrichment of HSP70-high stress-responsive T cells and PLTP⁺ tumor-associated macrophages, and depletion of memory T cells and cDC2-like dendritic cells, which show opposing associations with ICI outcomes. Integrating these findings, we derive a seven-gene brain metastasis-derived immune signature (BMIS) that is associated with ICI response and survival in NSCLC and metastatic urothelial carcinoma and provides information complementary to tumor mutational burden. These results highlight immune features specific to brain metastatic NSCLC and suggest candidate biomarkers and therapeutic avenues for improving immunotherapy in this high-risk population.