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Life sciences · Journal article
Frontiers in Immunology · October 2, 2026
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Background Non-small cell lung cancer (NSCLC) remains the leading cause of cancer mortality, and resistance to immune checkpoint inhibitors (ICIs) is largely driven by the tumor immune microenvironment (TIME), in which tumor-associated macrophages (TAMs) are major regulators. Objectives This review summarizes recent advances in understanding TAM heterogeneity, their contribution to immune resistance in NSCLC, and emerging therapeutic strategies targeting TAMs. Methods A literature search was conducted using PubMed and Google Scholar, focusing on studies published between 2021 and 2025. Key search terms included “non-small cell lung cancer”, “tumor immune microenvironment”, “macrophage heterogeneity”, “M1 macrophages”, “M2 macrophages”, “SPP1+ macrophages”, “TREM2+ macrophages”, “immune checkpoint inhibitor resistance”, “macrophage metabolic reprogramming”, and “TAM-targeted therapies”. Relevant studies addressing TAM heterogeneity, immune resistance, metabolic and molecular regulation, and therapeutic targeting in NSCLC were prioritized, while earlier studies were included where necessary to provide mechanistic context. Results Recent evidence demonstrates that TAMs comprise diverse functional subsets rather than a simple M1/M2 duality. Distinct populations including CXCL9+, SPP1+, C1Q+, and TREM2+ macrophages differentially regulate T-cell exclusion, immune checkpoint resistance, angiogenesis, and metabolic remodeling. Therapeutic approaches targeting CSF1R, CD47-SIRPα, metabolic pathways, nanoparticles, epigenetic regulators, engineered macrophages, and microRNA-based strategies show promise but remain limited by macrophage plasticity and compensatory immune mechanisms. Conclusion A comprehensive understanding of TAM heterogeneity within the tumor immune microenvironment provides a framework for overcoming immune resistance in NSCLC. Future therapeutic strategies should integrate biomarker-guided patient selection with combination approaches that simultaneously target macrophage plasticity and immune suppression.