Macrophages in lung cancer: principal factors, regulatory mechanisms, and therapeutic opportunities: a narrative review.

Background and Objective: Lung cancer is one of the most common malignant tumors in the world, with a high incidence and a poor prognosis. The current treatment methods are limited, and novel treatment strategies are needed. Macrophages, as innate immune cells, interact with lung cancer cells in the tumor microenvironment and can influence the occurrence and development of lung cancer. This paper reviews the role of macrophages in lung cancer in relation to polarization, exosomes, cytokines, cell pathways and genes, and clinical prognosis. Methods: A structured literature search of PubMed, Web of Science Core Collection, and Embase was conducted from database inception to February 6, 2026. This was supplemented by cross-checking in Google Scholar and manual screening of reference lists from key reviews and landmark studies. Two authors independently screened titles and abstracts, and full texts were assessed according to designated inclusion criteria. Key Content and Findings: A comprehensively review of the multifaceted roles of macrophages in lung cancer development, progression, and therapeutic response was conducted. The origin and phenotypic polarization of macrophages were examined, with the functional heterogeneity between antitumor M1 macrophages and protumor M2 tumor-associated macrophages (TAMs) within the tumor microenvironment emerging as a prominent topic. Another important theme was the crosstalk between macrophages and lung cancer cells mediated by exosomes, inflammatory cytokines, and key signaling pathways, including NF-κB, STAT3/STAT6, and PI3K/AKT, as well as gene regulatory mechanisms. These interactions collectively promote tumor growth, angiogenesis, metastasis, immune suppression, and therapy resistance. Furthermore, the clinical and prognostic significance of macrophage infiltration patterns and polarization status in patients with lung cancer was examined. Overall, the targeting of macrophage polarization and macrophage-related signaling networks emerged as a promising strategy for improving lung cancer diagnosis, prognosis assessment, and immunotherapeutic outcomes. Conclusions: Macrophages act as central regulators of lung cancer progression and therapeutic response through their remarkable plasticity within the tumor microenvironment. The balance between antitumor M1 and protumor M2 macrophages, shaped by exosomes, cytokines, signaling pathways, and gene regulation, critically influences tumor growth, metastasis, immune evasion, and prognosis. Targeting macrophage polarization and macrophage-related pathways represents a promising strategy for improving the diagnosis of patients with lung through achieving more accurate prognostic evaluation and greater treatment efficacy.