Tumor-associated macrophages beyond M1/M2 in NSCLC: spatially organized programs, therapy resistance, and translational targeting

Abstract

Tumor-associated macrophages (TAMs) are abundant and functionally diverse components of the lung tumor microenvironment (TME) and are associated with therapeutic response and resistance in non-small cell lung cancer (NSCLC). Durable responses to immune checkpoint inhibitors (ICIs) and targeted therapies remain limited, with TAM-associated immune evasion and therapy-refractory microenvironments representing potentially relevant components of this resistance landscape. This narrative review prioritizes evidence from human NSCLC specimens and clinically annotated cohorts, especially from single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, while integrating relevant mechanistic evidence from NSCLC experimental systems, animal models, and related cancer contexts. Moving beyond the M1/M2 paradigm, we synthesize convergent findings to describe recurring, niche-resolved TAM programs. Across NSCLC, we highlight recurrent SPP1 -associated, TREM2 -associated, and C1q/LAM-like macrophage programs as a practical framework for integrating recurrent TAM states across spatial and treatment contexts. We propose an integrative framework in which TAM state dynamics are associated with, and may contribute to, therapy-refractory phenotypes during (i) ICI therapy through immune exclusion, (ii) oncogene-targeted therapy through macrophage-associated bypass signaling and survival plasticity, particularly in EGFR-TKI resistance, and (iii) post-radiochemotherapy microenvironmental remodeling, with potential implications for residual disease ecosystems that require further clinical validation, particularly with respect to recurrence and relapse. TAM program signatures and spatial organization provide a rationale for investigating biomarker-guided stratification and macrophage-directed combination strategies targeting state–niche axes. Future work should prioritize clinically validated, state- and niche-resolved multimodal biomarkers and prospective translational studies to support rational pairing with ICIs and targeted therapies.