Traditional Chinese medicine in the prevention and treatment of lung cancer metastasis by regulating tumor-associated macrophages: a narrative review

Abstract

Background and objective: Lung cancer remains the leading cause of cancer-related mortality globally, with metastasis representing the principal determinant of poor clinical outcomes. Tumor-associated macrophages (TAMs), as key components of the tumor microenvironment (TME), play pivotal roles in modulating immune responses, tumor progression, and metastatic dissemination. Traditional Chinese medicine (TCM) has demonstrated potential in regulating TAM polarization, thereby inhibiting tumor metastasis. This review aims to comprehensively summarize the current evidence on how TCM modulates TAMs to prevent and treat lung cancer metastasis.

Methods: We conducted a systematic search of literature on TAMs, lung cancer metastasis, and TCM published between 2016 and 2025. Following initial screening of retrieved articles, relevant sources were cross-referenced to identify additional studies.

Key content and findings: This review presents a comprehensive summary of recent advances in the modulation of TAMs by TCM in the setting of lung cancer metastasis. TCM-derived compounds and classical herbal prescriptions have demonstrated the ability to reprogram TAMs from an immunosuppressive M2-like phenotype to an immunostimulatory M1-like phenotype. Mechanistically, these agents exert their effects by modulating multiple signaling pathways, including TLR4/NF-κB, STAT3/STAT6, PI3K/AKT, and STING/TBK1/IRF3 pathways, as well as key cytokine networks involving interleukin-6 (IL-6) and interferon-gamma (IFN-γ). Representative monomers, including curcumin, calycosin, and polyphyllin VII, as well as classical formulas such as Bu-Fei decoction (BFD) and Kejinyan decoction, exhibit anti-metastatic activity by reprogramming the immunosuppressive TME and enhancing anti-tumor immune responses.

Conclusions: TCM represents a promising strategy for suppressing lung cancer metastasis by targeting TAMs and restoring immune homeostasis. Future research should focus on the standardization of TCM formulations, mechanistic elucidation, and translational validation in clinical settings. Integrating TCM with contemporary immunotherapies may yield synergistic benefits and advance precision oncology for metastatic lung cancer.

Keywords: Tumor-associated macrophages (TAMs); lung cancer metastasis; polarization; traditional Chinese medicine (TCM).

Figure 1

Tumor microenvironment is composed of a diverse array of cell types and non-cellular components. Its core constituents include tumor cells, immune cells, fibroblasts, endothelial cells, mesenchymal stem cells, extracellular matrix, and metabolites. Among immune cells, T cells, NK cells, dendritic cells, B cells, and tumor-associated macrophages are the major players. Tumor-associated macrophages, one of the most abundant immune cell populations in the tumor microenvironment, are primarily derived from circulating monocytes. Tumor-associated macrophages typically polarize into two distinct phenotypes: the M1 phenotype, which exhibits anti-tumor activity, and the M2 phenotype, which promotes tumor progression. Their phenotypic polarization and functional properties are dynamically modulated by a variety of signaling molecules within the tumor microenvironment. The majority of tumor-associated macrophages tend to adopt the M2 phenotype, which is induced by cytokines secreted by Th2 cells, such as IL-4, IL-10, and IL-13. These M2-polarized tumor-associated macrophages facilitate tumor growth, invasion, and metastasis by secreting key factors, including VEGF, MMPs, and TGF-β. M2 macrophages can differentiate into four subtypes-M2a, M2b, M2c, and M2d-each playing distinct roles in response to specific stimuli within the tumor microenvironment. Symbols: arrows indicate direction of differentiation or cytokine signaling. Solid arrows show promoting signals; dashed arrows indicate intermediate or alternative differentiation. The figure is created via BioRender with credit. ICS, immune complexes; IFN, interferon; IL, interleukin; LIF, leukemia inhibitory factor; MMPs, matrix metalloproteinases; NK, natural killer; TGF-β, transforming growth factor-beta; Th1/Th2, T-helper type 1/2 cells; TNF, tumor necrosis factor; Treg, regulatory T cells; VEGF, vascular endothelial growth factor.

Figure 2

Mechanisms of TAM polarization regulated by traditional Chinese medicine in lung cancer. Symbols: red arrows, inhibitory signaling; green arrows, stimulatory signaling. The figure is created via BioRender with credit. Arg1, arginase-1; IL-10, interleukin-10; NO, nitric oxide; TAM, tumor-associated macrophages; TNF-α, tumor necrosis factor-alpha.