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

Introduction

Lung cancer, a malignant tumor characterized by high morbidity and mortality, poses a significant threat to human health and safety, emerging as a major challenge in global public health (1,2). Current treatments for lung cancer encompass surgery, radiotherapy, chemotherapy, targeted therapy, among others. Despite substantial advancements in modern medicine, recurrence and metastasis remain the primary causes of patient mortality (3). Consequently, the exploration of novel treatment strategies, particularly for the prevention and management of lung cancer metastasis, holds considerable clinical significance and scientific value.

The genesis and progression of lung cancer are influenced not only by the genomic and molecular attributes of the cancer cells themselves but are also significantly modulated by the tumor microenvironment (TME) (4). The TME constitutes a complex, multi-component ecosystem, primarily composed of tumor stromal cells, the blood and lymphatic systems, immune cells [including macrophages, tumor-infiltrating lymphocytes, dendritic cells (DCs), etc.], and non-cellular components [such as the extracellular matrix (ECM) and signaling molecules]. The dynamic interplay between tumor cells and immune components within the microenvironment is pivotal in the advancement of lung cancer. Among these, tumor-associated macrophages (TAMs), a crucial immune cell population within the TME, exhibit notable immunosuppressive characteristics and are involved in regulating tumor proliferation, invasion, and metastasis through the secretion of various cytokines and chemokines (5). Research indicates that within the TME, TAMs predominantly exhibit an M2 phenotype, and by secreting factors such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs), they foster tumor angiogenesis, ECM remodeling, and immune evasion, thereby hastening the process of tumor metastasis (6). Hence, elucidating the relationship between TAM polarization and lung cancer may unveil novel strategies for lung cancer treatment.

In traditional Chinese medicine (TCM), lung cancer is categorized under “cough”, “asthma”, and “lung distension” based on its clinical manifestations. The Lingshu: Thorn Festival True Evil states, “Deficiency evil resides deeply within the body, where cold and heat contend over prolonged periods.” According to TCM theory, the pathogenesis of lung cancer is characterized by root deficiency and superficial excess. The internal cause is attributed to the deficiency of Zhengqi, while the external cause involves the accumulation of pathogenic toxins internally. Consequently, in the prevention and treatment of lung cancer, TCM advocates the therapeutic principle of “fortifying the body and eliminating pathogenic factors”, with “strengthening the body and consolidating the root” at its core. The distinctive advantages and potential of TCM in tumor treatment have increasingly garnered attention. TCM can effectively modulate immune function and inhibit tumor progression through comprehensive regulation across multiple components, targets, and pathways. This article begins by exploring the mechanism through which TCM regulates TAM polarization to prevent lung cancer metastasis. It further discusses the molecular mechanisms by which TCM induces M1/M2 macrophage polarization and its regulatory impact on the TME, examines the current application status of TCM in the comprehensive treatment of lung cancer, and anticipates its clinical application prospects. The aim was to provide a novel theoretical foundation and therapeutic strategy for TCM in the prevention and treatment of lung cancer metastasis. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-380/rc).

Methods

A narrative review approach was employed to systematically search for studies related to “lung cancer”, “TAMs”, and “TCM” published between 2016 and 2025. The initial search was performed between March 10 and June 10, 2024, and was supplemented by a manual update in May 2025 to include relevant newly published articles. The databases searched included PubMed, Web of Science, Embase, Google Scholar, and China National Knowledge Infrastructure (CNKI). Boolean logic strategies combining Medical Subject Headings and free-text terms (e.g., “lung cancer” AND “TAMs” AND “TCM”) were applied to ensure a comprehensive retrieval of relevant literature. The inclusion criteria were as follows: (I) original experimental or clinical research articles; (II) studies focusing on the role of TAMs in the progression or metastasis of lung cancer; and (III) studies evaluating the regulatory effects of TCM or its active constituents on TAM polarization or the immune microenvironment. Exclusion criteria included conference abstracts, non-English publications, studies focused on non-lung cancer or non-TAM immune mechanisms, and studies lacking experimental validation. A comprehensive evaluation of eligible in vivo studies, mechanistically validated in vitro experiments, and clinical investigations was performed through manual screening of reference lists from the included articles, supplemented by expert consultation with co-authors and domain specialists. A total of 89 studies meeting all inclusion criteria were ultimately incorporated into this review (Table 1).

Macrophage overview

Macrophages are large cells derived from the directional differentiation of monocytes, playing a crucial role in inflammation, tumorigenesis, and immune regulation. Mature macrophages can differentiate into M1 and M2 subtypes depending on the microenvironment (7). Within the TME, macrophages are pivotal immune cells whose phenotypes and functions are intimately linked to tumor initiation, progression, invasion, and metastasis, hence they are also referred to as TAMs. Research has demonstrated that macrophages in the microenvironment exhibit significant heterogeneity and plasticity (8).

It is well established that the polarization of TAMs relies on helper CD4⁺ T (Th) cell subsets, which activate M1 and M2 macrophages through distinct classical pathways. Specifically, M1 macrophages predominantly create an inflammatory microenvironment mediated by Th1 molecules such as interferon-gamma (IFN-γ), lipopolysaccharide (LPS), and granulocyte-macrophage colony-stimulating factor (GM-CSF) (9). Previous research revealed that Th1 molecules can activate transcription factors, including NF-κB, signal transducer and STAT1, and IRF1, facilitating their translocation to the nucleus and binding to target gene promoters, thereby inducing M1 polarization in macrophages (10). Additionally, nitric oxide (NO) and reactive oxygen species (ROS) generated by M1 macrophages can inhibit tumor growth. Conversely, M2 macrophages are regulated by transcription factors such as STAT6, peroxisome proliferator-activated receptor (PPAR)-γ, and suppressor of cytokine signaling 2 (SOCS2), and they secrete anti-inflammatory factors like interleukin (IL)-10, transforming growth factor (TGF)-β, and arginase 1 (Arg1) to exert anti-inflammatory effects. Currently, it is widely accepted that the M2a subtype primarily contributes to tissue fibrosis, M2b exhibits carcinogenic properties in non-small cell lung cancer (NSCLC), M2c is involved in tissue remodeling, and M2d promotes angiogenesis (11,12).

Research indicated that M2 macrophages are not only pivotal in tumor immune evasion but also significantly contribute to tumor progression by facilitating tumor cell proliferation, differentiation, invasion, and metastasis (13). Pritchard et al. demonstrated that both the M2a and M2c subtypes can augment the invasive capacity of A549 cells, whereas M1 macrophages can suppress tumor growth by inhibiting pro-tumor factors such as fibrinogen and TGF-β (14). In summary, M2 macrophages serve as crucial regulatory molecules in tumor initiation and progression and are also vital indicators for assessing tumor malignancy and prognosis.

Macrophages and lung cancer

Alveolar macrophages (AMs) in lung cancer progression

AM regulation of the TME

AMs, the resident immune cells of lung tissue, are primarily categorized into two subsets: tissue-resident AMs (TRAMs) and monocyte-derived AMs (MoAMs) (15). Under inflammatory conditions, precursor macrophages derived from erythro-myeloid progenitors (EMPs) are rapidly recruited to the alveolar space and other inflamed tissues to regulate the inflammatory response (16). As a critical component of the respiratory system’s innate immune barrier, AMs contribute to the pathogenesis of various chronic lung diseases via their distinct immunological functions.

AMs play a pivotal regulatory role in physiological processes, including maintenance of lung homeostasis, immune surveillance, pathogen clearance, and tissue repair (17). Notably, AMs exert dual regulatory effects during lung cancer development. Studies demonstrated that AMs isolated from lung cancer patients, upon stimulation with including IFN-γ or GM-CSF, significantly upregulate the secretion of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, IL-6, and IL-1β, thereby enhancing anti-tumor immune responses (18,19). However, clinical observations indicate that during the progression of NSCLC, AMs display marked functional exhaustion, characterized by reduced phagocytic activity and diminished secretion of immunostimulatory factors (20). This dynamic functional shift suggests that AMs may facilitate tumor progression by contributing to the formation of an immunosuppressive TME and disrupting immune homeostasis.

AMs in lung cancer metastasis

During lung cancer progression, AMs in the NSCLC microenvironment tend to differentiate into TAMs, and this phenotypic transition exerts multifaceted regulatory effects on tumor cell proliferation, invasion, and metastasis (21,22). These macrophages are involved not only in the malignant progression of the primary tumor but also in mediating the distal dissemination of tumor cells. Studies have shown that the infiltration level of M2-polarized AMs at primary tumor sites is significantly positively correlated with metastatic risk in both NSCLC and small cell lung cancer (SCLC) models (23,24). This process further enhances tumor immune evasion by recruiting immunosuppressive cell populations, such as regulatory T cells (Tregs). Moreover, AMs establish complex crosstalk with stromal components, including fibroblasts and endothelial cells, within the TME to sustain tumor viability and metastatic potential through the promotion of neovascularization (25).

TAMs in lung cancer

Polarization and functions of TAMs

TAMs exhibit plasticity, primarily manifesting as M1 (classically activated) and M2 (alternatively activated) polarization phenotypes, a process analogous to the Th1-Th2 differentiation of T cells (26). Peripheral blood monocyte-derived TAMs are recruited to the TME by tumor-derived chemokines and undergo phenotypic polarization in response to local microenvironmental stimuli.

M1 TAMs are induced to differentiate by factors, IFN-γ, TNF-α, and GM-CSF, and they play a role in activating Th1-type immune responses (27). This phenotype exerts anti-tumor effects through the secretion of effector molecules such as NO and ROS, as well as pro-inflammatory factors including IL-1β, IL-6, IL-12, C-X-C motif chemokine ligand 9 (CXCL9), CXCL10 and TNF-α, in conjunction with major histocompatibility complex (MHC) molecules (28). The expression of surface markers CD68, CD80, and CD86 further corroborates their immune-activating properties. Conversely, M2 TAMs are induced by factors such as IL-10 and TGF-β, which activate Th2-type immune responses and facilitate tumor progression (29). By upregulating anti-inflammatory mediators such as IL-10, TGF-β, C-C motif chemokine ligand 17 (CCL17), and CCL22, as well as expressing surface markers including CD206, CD204, and CD163, M2 TAMs contribute to key pathological processes such as tumor invasion, metastasis, angiogenesis, and immunosuppression (30).

Dynamic changes of TAMs in lung cancer progression

The number, phenotype, and microstructural characteristics of TAMs serve as crucial biological markers for lung cancer prognosis. Research has demonstrated that the polarization state of TAMs is significantly associated with the progression of NSCLC (31). TAMs facilitate NSCLC metastasis through the secretion of exosomes and exhibit dynamic phenotype switching within the TME (32). Specifically, M1 TAMs exert anti-tumor effects by generating effector molecules such as NO and ROS. However, the pro-inflammatory factors secreted by M1 TAMs may concurrently increase the genomic instability of tumor cells, thereby indirectly fostering tumor progression (33). Conversely, the polarization of M2 TAMs enhances NSCLC migration and angiogenesis. Nevertheless, the transition of M2 TAMs to M1 TAMs can suppress VEGF expression and angiogenesis. This suppression can remodel the TME and further drive the polarization of M2 TAMs to M1 TAMs, establishing a positive feedback regulatory mechanism (34).

CSF-1 secreted by tumor cells can induce the polarization of TAMs to the M2 phenotype during lung cancer progression. Clinical studies have revealed that the number of AMs in the bronchoalveolar lavage fluid (BALF) of lung cancer patients is significantly elevated, yet their phagocytic function is diminished, and the expression of surface markers such as human leukocyte antigen-DR (HLA-DR), CD83, and intercellular adhesion molecule 1 (ICAM-1) is reduced. Concurrently, the expression levels of inflammatory factors including IL-1 and TNF-α are markedly down-regulated (20,35). M1 TAMs predominate in the early stages of lung cancer, whereas M2 TAMs are predominantly enriched in the advanced stages. Thus, the dynamic transition in the polarization phenotype of TAMs is a pivotal factor driving lung cancer progression. The changes of TAMs in the lung cancer microenvironment are shown in Figure 1.

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.

Molecular mechanisms of TAM-driven lung cancer metastasis

As crucial components of TME, TAMs play a pivotal role in promoting tumor invasion and metastasis through multiple mechanisms. These include inducing epithelial-mesenchymal transition (EMT), facilitating angiogenesis, and suppressing anti-tumor immune responses. Consequently, elucidating the mechanisms by which TAMs promote tumor metastasis may provide a theoretical foundation for developing preventive and therapeutic strategies against metastatic progression.

TAMs promote tumor invasion and metastasis

The metabolic features of the TME significantly influence the spatial distribution and functional properties of TAMs. Due to the distinct metabolic characteristics of tumor tissues, TAMs are preferentially enriched in hypoxic regions and at tumor-normal tissue interfaces, particularly in perivascular areas. This spatial distribution creates favorable conditions for tumor cell invasion and metastasis (36). Research demonstrated that TNF-α secreted by TAMs can significantly upregulate MMP expression in both tumor cells and stromal cells. The overexpression of MMPs facilitates ECM and basement membrane degradation, compromising tissue structural integrity and promoting tumor metastasis (37).

EMT represents a crucial mechanism in tumor metastasis. Numerous studies confirmed that various immune cells within the TME, including macrophages, neutrophils, lymphocytes, and myeloid-derived suppressor cells, can significantly promote tumor cell EMT through the secretion of diverse cytokines and chemokines (38,39). Furthermore, cytokine-mediated signaling pathways play a pivotal role in regulating EMT. Inflammatory factors such as IL-1β, IL-6, and TNF-α induce the expression of EMT-related transcription factors by activating multiple signaling pathways, including PI3K/PKB, NF-κB, and STAT3 (40).

TAMs promote angiogenesis

TAMs play a crucial role in tumor angiogenesis, with their presence demonstrating a significant positive correlation with angiogenic activity (41). TAMs stimulate vascular endothelial cells to secrete VEGF through the synthesis of WNT7b, while upregulating pro-angiogenic factors such as GM-CSF and basic fibroblast growth factor (bFGF), thereby promoting tumor angiogenesis (42). Endothelial cells within the TME serve as the fundamental basis for tumor angiogenesis. Salmaninejad et al. demonstrated that TAMs not only induce neovCascularization in tumor regions but also promote lymphatic vascularization through the high expression of VEGF. Furthermore, TAMs can directly modulate endothelial cell function, facilitating vascular sprouting and remodeling processes (43).

TAMs promote immunosuppressive microenvironment formation

The immunosuppressive role of TAMs in the TME has been extensively investigated. TAMs exert their immunosuppressive effects through dual mechanisms: direct cytotoxic effects on T cells and indirect suppression of effector T cell activity by promoting Treg proliferation (44). TAMs significantly inhibit immune responses through IL-10 secretion, inducing the expression of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on T cells. The binding of these inhibitory receptors to their respective ligands-programmed death ligand-1 (PD-L1), PD-L2, CD80, and CD86-suppresses T cell activation and proliferation, ultimately leading to T cell exhaustion and programmed cell death (45). Furthermore, TAMs secrete various chemokines, cytokines, and enzymes that directly impair CD8⁺ and CD4⁺ T cell effector functions while recruiting Tregs to the TME, thereby enhancing immunosuppression (46).

TCM and macrophage polarization in the inhibition of lung cancer metastasis

TAMs regulated by TCM

Accumulating evidence indicates that TCM exhibits unique therapeutic potential in modulating the TME of solid malignancies. Its mechanisms of action include inhibiting tumor angiogenesis, reducing chemotherapy resistance, reversing the immunosuppressive microenvironment, and enhancing anti-tumor immune responses through the regulation of TAMs (47). TCM exerts multi-target anti-tumor effects: certain components directly suppress tumor cell proliferation, whereas others indirectly impede tumor growth, invasion, and metastasis via immune system modulation (48). Pharmacological studies have identified key bioactive compounds in TCM, such as glycosides, alkaloids, and polysaccharides, that modulate macrophage activity. These compounds activate critical signaling pathways, including TLR4, NF-κB, and MAPK, primarily through interactions with cell surface receptors. Pathway activation enhances phagocytic activity, stimulates ROS and NO production, and upregulates anti-tumor cytokine expression in TAMs, thereby inducing systemic anti-tumor immune regulation (49,50).

Bioactive compounds in TCM promote the polarization of TAMs from the pro-tumoral M2 phenotype to the anti-tumoral M1 phenotype via modulation of canonical signaling pathways. Li et al. showed that Ganoderma lucidum polysaccharide enhances NO levels in macrophages and induces macrophage autophagy through the activation of the TLR4/NF-κB/MAPK pathway (51). Sheik et al. demonstrated that astragaloside IV suppresses lung cancer proliferation and invasion in murine models through inhibition of the AMPK signaling pathway, downregulation of IL-13 and IL-4 expression, and reduction of M2-type TAM proportion (52). Zhao et al. demonstrated that matrine inhibits the M2 macrophage-induced EMT through suppression of the PI3K/AKT signaling axis, while simultaneously potentiating T cell-mediated anti-tumor immunity through functional modulation of TAMs (53). Shang et al. discovered that Schisandra chinensis polysaccharide modulates the expression of NO, TNF-α, and other factors by activating the TLR4 signaling pathway, thereby exerting anti-tumor effects (54). Furthermore, TCM can reconfigure the immunophenotypes of TAMs by regulating the cytokine network within the TME, suppressing the secretion of pro-tumor factors such as IL-10 and TGF-β, and enhancing the production of anti-tumor factors like IFN-γ and IL-12. Notably, certain TCM components can also influence the transcriptional activity of TAM-related genes by modulating epigenetic mechanisms, including histone modification and DNA methylation, further driving their polarization toward the M1 phenotype (55). Jiang et al. demonstrated that curcumin promotes the polarization of TAMs toward an immunostimulatory M1 phenotype by selectively inhibiting histone deacetylases 3 and 4 (HDAC3 and HDAC4), thereby inducing chromatin fragmentation and upregulating M1-associated genes. Concurrently, curcumin suppresses M2 polarization by inhibiting the NF-κB and STAT3 signaling pathways, thereby enhancing anti-tumor immunity (56). These multi-pathway regulatory mechanisms collectively form the molecular foundation for TCM-induced TAM polarization, offering novel insights for lung cancer immunotherapy.

TCM and the inhibition of lung cancer metastasis: mechanistic insights

TCM modulates TAM function through multiple mechanisms, including the activation of anti-tumor macrophages, inhibition of TAM recruitment and activation, and promotion of M1-type TAM polarization. Certain TCM formulations directly inhibit tumor cell proliferation, while others exert indirect antitumor effects by regulating the immune system, thereby suppressing tumor growth, invasion, and metastasis (57). The inhibition of monocyte recruitment represents a crucial target in anti-tumor immunotherapy, offering an effective strategy for blocking tumor progression.

Studies demonstrated that primary lung cancer cells recruit peripheral blood macrophages through the secretion of bioactive substances, including exosomes, integrins, and chemokines, which subsequently infiltrate the TME and differentiate into TAMs (58,59). This recruitment process involves multiple key molecules, such as CCL2, IL-4, TGF-β, CSF-1, and immunoglobulin G receptor-recognized immune complexes. The recruitment of TAMs is primarily regulated by signaling pathways, including the CCL2-CCR2 axis, CXCL12-CXCR4 axis, and CSF1-CSF1R axis (26). These pathways not only mediate macrophage migration and differentiation but also contribute to tumor immune evasion and angiogenesis.

TCM exerts anti-tumor effects through immunomodulation of TME components. Specifically, TCM enhances the expression and functional activity of CD4⁺ T cells, CD8⁺ T cells, natural killer (NK) cells, and DCs, while suppressing M2 polarization of TAMs and the immunosuppressive function of Tregs, thereby remodeling the immunosuppressive TME. This process inhibits immune escape of lung cancer cells and ultimately blocks tumor invasion and metastasis (60,61). Furthermore, the functional polarization of TAMs is precisely regulated by multiple cytokines and signaling proteins within the TME. TCM modulates TAM polarization and functional characteristics by differentially regulating the expression of these key molecular mediators, ultimately suppressing lung cancer metastasis. Li et al. revealed that ginsenosides exert anti-tumor effects by regulating TAM differentiation states and their interactions with the TME, with their anti-tumor mechanisms primarily depending on indirect modulation of the immune microenvironment (62). Polyphyllin VII promotes M1 macrophage polarization and inhibits STAT3 phosphorylation through activation of the STING/TBK1/IRF3 signaling pathway, a mechanism that is strongly associated with STING protein expression levels (63) (Figure 2).

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.

TCM-mediated regulation of the TME

TCM represents a promising therapeutic strategy for modulating the TME. While some TCM formulations directly induce tumor cell apoptosis, a greater number exert anti-tumor effects through immunomodulatory pathways. Despite their low cytotoxicity, these agents significantly enhance the functional activity of immune effector cells and suppress immunosuppressive cells, thereby achieving anti-tumor outcomes (64). Recent studies indicate that TCM mitigates tumor initiation and progression by reducing the toxic side effects of conventional treatments such as radiotherapy and chemotherapy, while enhancing their synergistic efficacy. TCM has also demonstrated significant potential in inhibiting tumor recurrence and metastasis (65,66). Within the TME, TAMs typically exhibit M2 polarization, characterized by low antigen-presenting capacity, which facilitates immune escape (67). Consequently, TCM interventions aimed at “strengthening” the TME promote the conversion of M2 TAMs to the M1 phenotype.

Numerous TCM compounds exhibit significant anti-tumor effects, and preliminary experimental studies have partially elucidated their mechanisms of action. Bu-Fei decoction (BFD), a classic formulation widely employed in clinical settings to alleviate lung cancer-related symptoms, interferes with TAM-cancer cell crosstalk by inhibiting the IL-10/PD-1 signaling axis, thereby exerting anti-tumor effects (68). Pang et al. demonstrated that BFD reduces pulmonary inflammation and fibrosis in murine models while downregulating PD-1, IL-10, and CD206 expression, consequently inhibiting the tumor-promoting effects of M2-type TAMs (69). Accumulating evidence confirms that multiple bioactive components in BFD possess notable anti-tumor properties. Notably, Astragalus polysaccharide PG2 (APS-PG2) effectively suppresses tumor proliferation and metastasis in murine models by modulating macrophage-mediated inflammatory responses and angiogenesis (70). Wu et al. reported that calycosin exhibits IL-6 inhibitory activity in TAMs within murine models, contributing to its in vivo anti-tumor efficacy (71). Therefore, calycosin represents a promising therapeutic candidate targeting TAMs. Kejinyan decoction, an empirical formulation comprising 13 medicinal herbs, is extensively utilized in lung cancer management. Chen et al. employed RNA sequencing in C57BL/6 mouse Lewis lung cancer models, revealing that Kejinyan decoction remodels the TME through inflammatory factor reduction and glucose metabolic reprogramming, consequently altering macrophage and tumor cell biology while promoting M1 macrophage polarization (72).

Clinical application and prospects of TCM in lung cancer metastasis prevention and treatment

Clinical validation of TCM for lung cancer

Based on in vitro models of the premetastatic lung cancer microenvironment and evidence from multicenter clinical studies, key molecular mechanisms by which TCM regulates anti-tumor immune responses have been elucidated. TCM offers a novel scientific rationale for the prevention and treatment of lung cancer by modulating the host-tumor interface and remodeling the immunosuppressive microenvironment (73). TCM has demonstrated significant clinical value as an adjuvant therapy following tumor resection, effectively prolonging disease-free survival (DFS) and mitigating systemic toxicities commonly associated with conventional therapies, such as vascular toxicity, immunosuppression, gastrointestinal disturbances, and bone marrow suppression (74).

The current clinical evidence base is well-established, encompassing high-level evidence from multicenter randomized controlled trials (RCTs), meta-analyses, and cohort studies. For example, in the treatment of NSCLC, compound Kushen injection (CKI), when used as an adjuvant to platinum-based chemotherapy (PBC), exerts synergistic anti-tumor effects by enhancing immune function and inhibiting tumor cell proliferation and metastasis. A meta-analysis of 25 RCTs (n=2,460) demonstrated that CKI in combination with PBC significantly increased peripheral T lymphocyte subsets (CD3⁺, CD4⁺, CD8⁺) and the CD4⁺/CD8⁺ ratio in patients with NSCLC (75). Another clinical study (n=75) indicated that adjuvant treatment with TCM compounds, including Yiqi Qingre decoction, Nourishing Yin Qingre decoction, and Yiqi Yangyin Qingre decoction, significantly prolonged DFS and reduced recurrence and metastasis in patients with stage IIIA NSCLC after complete resection. The underlying mechanism may involve downregulation of CTLA-4⁺ Tregs (76). Additionally, a retrospective study involving 67 patients with limited-stage SCLC (LS-SCLC) confirmed that TCM formulations, such as Liujunzi decoction, Erchen decoction, Siwu decoction, Qianjin Weijing decoction, Shengmai Powder, and Shashen Maidong decoction, combined with PBC significantly improved patient prognosis, delayed disease progression, and prolonged survival compared to chemotherapy alone (77).

Synergy between TCM and immunotherapy

In recent years, immunotherapy has emerged as a pivotal modality in cancer treatment, particularly for lung cancer. Immune checkpoint blockade (ICB) has demonstrated remarkable clinical efficacy (78). This therapeutic approach primarily employs immune checkpoint inhibitors (ICIs) to block interactions between checkpoint molecules and their ligands, thereby reactivating suppressed immune cells and restoring their cytotoxic activity against tumor cells. Representative ICIs, such as PD-1, PD-L1, and CTLA-4, have achieved substantial clinical success and are now widely applied in the treatment of various malignancies (79). However, the efficacy of immunotherapy as a monotherapy is frequently constrained by the complex immunosuppressive mechanisms of the TME, particularly the modulatory effects of immunosuppressive cells such as TAMs (80).

TCM exhibits unique potential in remodeling the TME and enhancing immune function through its multi-target actions and holistic regulatory properties. It can synergize with modern immunotherapy to enhance clinical efficacy (81). Studies shown that TCM can significantly potentiate the efficacy of ICB therapy by modulating the expression of PD-1, PD-L1, and related downstream signaling molecules. This effect is achieved through the upregulation of immune-stimulatory factors and downregulation of immunosuppressive mediators (82,83). Using a lung cancer model, Pan et al. found that the Qingfei Jiedu formula reduced PD-L1 expression in tumor tissues by modulating the expression of key genes involved in signaling pathways, including HIF-1, EGFR, transcription factor JUN, and NF-κB. This modulation enhanced CD8⁺ T cell infiltration and subsequently strengthened the anti-tumor immune response (84). Huang et al. further demonstrated that the combination of ginseng polysaccharides and anti-PD-1 monoclonal antibody exhibited superior anti-tumor activity in a Lewis lung carcinoma mouse model. This combinatorial regimen not only increased the CD8⁺/CD4⁺ T cell ratio but also effectively suppressed Tregs and alleviated tumor-induced immunosuppression (85) (Table 2).

Targeted therapy strategies via macrophage polarization

Recent advances in immunology, TME research, and single-cell omics have significantly enhanced our understanding of the functional states and phenotypic diversity of TAMs (86). The classical M1/M2 polarization model is insufficient to explain the complex regulatory roles of TAMs in tumorigenesis, metastasis, and immune evasion. A recent study revealed that, beyond the classical polarized phenotypes, TAMs encompass diverse functional subsets with immunosuppressive characteristics, including TREM2⁺, FOLR2⁺, and MARCO⁺ macrophages (87). These subtypes are highly enriched in the lung cancer microenvironment and are closely associated with disease progression and resistance to immunotherapy, thereby representing promising targets for therapeutic intervention (88). Future research may integrate the screening of bioactive components from TCM, identification of TAM subtype-specific targets, and spatial transcriptomics to facilitate the integration of TCM with contemporary tumor immunotherapy. Targeting and modulating TAM polarization-a critical nexus linking core immune mechanisms with TCM-based therapeutic strategies-may offer a more precise and translationally viable approach for preventing and treating lung cancer metastasis.

Conclusions

As pivotal immunomodulatory cells, TAMs play a central role in the initiation, progression, and metastasis of lung cancer, emerging as a critical focus in immunotherapy research. TAMs exert negative immunomodulatory effects by promoting tumor cell proliferation, angiogenesis, and distant metastasis, thereby exacerbating disease malignancy. In recent years, significant advancements have been made in understanding how TCM regulates TAMs to prevent and treat lung cancer. The research emphasis has progressively shifted from assessing the overall efficacy of TCM to elucidating the molecular mechanisms underlying its multi-target, multi-pathway regulation of TAM polarization, particularly in TAM recruitment, phenotypic switching, and interactions with the TME. Monomeric compounds, active constituents, and formulations derived from TCM can modulate the expression of relevant proteins and genes via multiple signaling pathways. These agents inhibit M2 polarization of macrophages and promote their repolarization toward the M1 phenotype. This process involves coordinated modulation of multiple signaling cascades, including the TLR4/NF-κB/MAPK and STAT3/6 pathways, ultimately resulting in multifaceted anti-tumor effects.

Although previous studies demonstrated the potential of TCM to modulate TAMs and suppress lung cancer metastasis, several limitations remain. First, most current studies are based on in vitro models or murine systems, which fail to fully capture the complexity of the human TME. Second, the complex composition of TCM and the limited mechanistic understanding of individual bioactive constituents hinder precise target identification. In addition, the lack of large-scale clinical trials and standardized immunological evaluation criteria impedes the translation of basic research into clinical application. Future efforts should focus on standardizing research design, elucidating target mechanisms in greater detail, and developing translational frameworks for TCM-based TAM-targeted therapies.

In addition, considering the complex immunological landscape of the TME, future research should go beyond examining TAM polarization in isolation and instead systematically explore the dynamic interactions between TAMs and other immune and stromal cell populations, including T cells, DCs, and cancer-associated fibroblasts. Emerging technologies, including single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and multiplexed imaging, will be essential for resolving cellular heterogeneity and elucidating the spatiotemporal regulatory networks within the TME. Integrating these advanced techniques with the pharmacological analysis of TCM will provide a more comprehensive understanding of how TCM modulates the immune landscape and may contribute to the development of more precise immunotherapeutic strategies for the prevention and treatment of lung cancer metastasis.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-380/rc

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