Divergent CD45? immune landscapes shape the lung tumor microenvironment
Background: The lung tumor microenvironment (TME) plays a crucial role in the progression and metastasis of lung cancer. It consists of various cell types that interact in complex ways to influence tumor behavior. CD45+ cells, as a component of the TME, have complex and multifaceted roles in lung cancer. The balance between the anti-tumor and pro-tumor functions of CD45+ cells can significantly affect lung cancer outcomes. Understanding these roles is essential for developing targeted therapies that harness the beneficial effects of CD45+ cells while mitigating their harmful effects.  Methods: We performed single-cell RNA sequencing of sorted CD45? immune cells from healthy lungs, orthotopic LLC1 tumors, and KrasLA2 (Kras) genetically engineered tumors. Analyses included immune composition, transcriptional programs, differentiation trajectories, metabolic states, and ligand-receptor-based intercellular communication networks.  Results: Four major immune compartments, B cells, T cells, NK cells, and macrophages, underwent model-specific remodeling. LLC1 tumors showed B cell expansion and T and NK cell reduction, with inflammatory, stress-response, and NF-?B/TNF-dominant programs. KrasLA2 tumors retained a balanced immune composition but exhibited metabolic rewiring, elevated antigen-presentation signatures, and selective intercellular signaling. Subclustering revealed specialized changes across B cell (resting, mature, pre-Bcr, late pro-B, plasma), T cell (Cd4?, Cd8?, memory, activated, Treg, Th17), NK cell (Fcgr3high, Fcgr3low, Xcl1?), and macrophage (Ace?, Bcr?, Ccr2?, Cd3?, metabolic, MHCII?) subsets. Ligand-receptor analyses highlighted dense inflammatory networks in LLC1 tumors versus metabolically tuned signaling in KrasLA2 tumors.  Conclusion:  Distinct CD45? immune landscapes, characterized by inflammatory suppression in LLC1 and metabolic adaptation in KrasLA2 tumors, shape lung tumor biology. This atlas identifies genotype-specific immune vulnerabilities with potential relevance for precision immunotherapy in non-small cell lung cancer.