Single-cell analysis reveals multicellular immune coordination and drug targets in driver-mutated NSCLC

Non-small cell lung cancer (NSCLC) harboring driver mutations rely on specific oncogenic signaling pathways to promote tumor progression and remodel immune responses, yet the role of multicellular immune coordination within the tumor immune microenvironment (TIME) remains unclear. We performed single-cell transcriptomic profiling of ~ 200,000 cells from 45 untreated NSCLC patients with seven driver mutations and identified five functionally distinct multicellular modules (CM1–5). Strikingly, the invasive CM2 and CM5 were strongly associated with poor prognosis. CM2 was enriched in EGFR- and MET-driven brain metastases and featured dense astrocytic–myofibroblast interactions, with pro-invasive signals (SPP1, PTN, PSAP) and metabolic reprogramming fostering a permissive metastatic TIME. CM5 was prevalent in ROS1-, KRAS-, and EGFR-mutant tumors and comprised heterogeneous myeloid and endothelial populations enriched for immunosuppressive and pro-angiogenic signals, including MIF, GALECTIN, and RETN. We further developed a driver mutation–specific prognostic signature (DMSP.sig) based on receptor–ligand interactions and core transcriptional regulators, which robustly stratified patient survival and identified candidate therapeutic agents. Collectively, our study reveals driver-shaped TIME subtypes with implications for risk assessment and precision immunotherapy in high-risk NSCLC.