Single-Cell Transcriptomic Mapping of Immune Evasion Pathways in Treatment-Resistant Non-Small Cell Lung Cancer

Background Immune checkpoint inhibitors have transformed the treatment landscape of non-small cell lung cancer (NSCLC); however, primary and acquired resistance remain major clinical challenges. Immune evasion in NSCLC is increasingly recognized as a complex, dynamic process driven by tumor heterogeneity and adaptive remodeling of the tumor microenvironment. Conventional bulk profiling approaches are limited in resolving this complexity, underscoring the need for higher-resolution methodologies. Objective This review aims to synthesize current evidence on how single-cell transcriptomic approaches have advanced the understanding of immune evasion mechanisms in treatment-resistant NSCLC, with a focus on tumor-intrinsic programs, immune cell dysfunction, and intercellular communication networks. Methods A structured narrative review with systematic elements was conducted, analyzing peer-reviewed studies employing single-cell RNA sequencing and related single-cell technologies in human NSCLC. Studies were evaluated for their insights into immune escape pathways, resistance to immunotherapy, and translational relevance. Results Single-cell transcriptomic analyses reveal profound intratumoral and immune heterogeneity in treatment-resistant NSCLC. Resistant tumors harbor distinct malignant cell states characterized by impaired antigen presentation, dysregulated interferon signaling, and lineage plasticity. Within the immune compartment, hierarchical T-cell exhaustion, depletion of progenitor-like exhausted T cells, and expansion of immunosuppressive myeloid populations—particularly tumor-associated macrophages—emerge as dominant features of resistance. Ligand–receptor interaction analyses further demonstrate coordinated immunosuppressive communication networks that sustain immune escape at a systems level. Several single-cell–defined cellular states correlate with poor response to immune checkpoint blockade and adverse clinical outcomes. Conclusion Single-cell transcriptomics has fundamentally reshaped the conceptual framework of immune resistance in NSCLC, redefining it as a multicellular, dynamic ecosystem rather than a single-pathway phenomenon. These insights provide a strong biological rationale for developing biomarker strategies and rational combination therapies that target both tumor-intrinsic adaptations and the immunosuppressive microenvironment. Continued integration of single-cell technologies into translational and clinical research is essential to overcome immunotherapy resistance and improve patient outcomes in NSCLC. Keywords: Non-small cell lung cancer; Single-cell RNA sequencing; Immune evasion; Immunotherapy resistance; Tumor microenvironment