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

Introduction

Lung cancer, as one of the most common malignant tumors in the world, has the highest global incidence and cancer-related mortality (1). In China, it is the leading cause of cancer-related death in men and women, with China accounting for 40% of all lung cancer deaths in the world (2). The incidence and mortality rates of lung cancer have been increasing over the past decades, imposing a substantial financial and emotional burden on afflicted patients (3).

The World Health Organization divides lung cancer into two main categories: non-small cell lung cancer (NSCLC; 80–85% of cases) and small cell lung cancer (SCLC; 15% of cases). Approximately, 40% of NSCLC are adenocarcinomas, 25% to 30% squamous cell carcinomas, and 10% to 15% large cell carcinomas (4). Conventional cancer treatments, including surgery, radiotherapy, and chemotherapy, provide limited improvement in overall survival (OS) and significant adverse effects. Moreover, targeted therapies have varying side effects and do not consistently yield therapeutic effects. Consequently, more effective strategies are needed to manage and treat patients with lung cancer. In recent years, the growing understanding of immune-escape mechanisms has brought attention to the immune system’s substantial involvement in the development and progression of lung cancer. Therefore, immunotherapy has gradually emerged as a potent therapeutic strategy in lung cancer (5,6).

A large body of clinical and experimental evidence indicates that macrophages contribute to the promotion of tumorigenesis and malignant progression. Preclinical studies have demonstrated the efficacy of therapeutic modalities that target macrophages in cancer treatment (7). Therefore, an in-depth investigation into the classification and function of macrophages may aid in developing novel therapeutic strategies for the treatment and control of tumors. Macrophage-associated cellular immunotherapy thus represents a fresh and effective treatment modality for patients with lung cancer, especially those at the advanced stage or who do not respond well to conventional treatments. We thus conducted a review to summarize the literature related to the origin and polarization of macrophages and the interaction between exosomes and inflammatory factors between lung cancer cells and macrophages. Some exemplary findings are as follows: exosomes secreted from lung cancer deliver miR-23a to induce the transformation of macrophages to M2 (8). Moreover, lung cancer exosomes promote the transformation of macrophages to protumor phenotype by transferring metabolic enzymes and metabolites (9). Clinically, inhibition of colony-stimulating factor 1 receptor (CSF-1R) blocks the recruitment and survival of tumor-associated macrophage (TAM) and reduces the number of M2-type TAMs (10). In addition, this review summarizes some of the classical cell signal transduction pathways and genes shared by lung cancer and macrophages and further discusses the role of macrophages in lung cancer development. Overall, it is hoped this review can serve as a reference to prompt the development of novel strategies and identification of targets in the immunotherapy of lung cancer. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0418/rc).

Methods

A narrative review on the role of macrophages in lung cancer was conducted, with key topics being polarization, exosome-mediated communication, inflammatory cytokines, canonical signaling pathways, gene-associated mechanisms, and clinical/prognostic implications. 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 a cross-check with Google Scholar and the manual screening of reference lists from key reviews and landmark studies. The search strategy included combining Medical Subject Headings (MeSH) and free-text keywords related to macrophages/TAMs and lung cancer (NSCLC/SCLC) with topic-specific terms (e.g., M1/M2 polarization, exosomes/extracellular vesicles, cytokines, NF-κB, STAT3/STAT6, PI3K/AKT, and immune checkpoints). The overall literature search strategy is summarized in Table 1. Original studies and high-quality reviews/meta-analyses relevant to macrophages in lung cancer that were peer-reviewed and published in English were included, with literature on non-relevant cancer types or lacking content on macrophages/TAMs being excluded. Titles/abstracts and full texts were screened by Y.T. and Y.W., with disagreements resolved through discussion with Yan Zhang; all authors approved the final set of the included references.

Origin and phenotypic polarization

Origin of macrophages

Macrophages play an important role in the innate immune system and respond rapidly to infection. Macrophages are present in the tissues of almost all healthy adults and arise either from embryonic precursors before birth (yolk sac or fetal liver) or from monocyte precursors of adult hematopoietic origin (11). During development, progenitor cells from the yolk sac are found throughout all tissues, producing progeny that persist throughout life, and are primarily regulated by CSF1R and its ligands IL34 and CSF1 (12). Later in development, the main source of macrophages is hematopoiesis in the fetal liver (13). Hematopoietic stem cells (HSCS) from adult bone marrow can differentiate into different cell types, including circulating monocytes, dendritic cells (DCs), and granulocytes (14). Monoblasts produce promonocytes via interleukin (IL)-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), or granulocyte colony-stimulating factor (G-CSF), which then differentiate into mature circulating monocytes. Following this, mature circulating monocytes migrate from the bone marrow into the blood (15). Due to their heterogeneity, circulating monocytes enter different organs and tissues from the blood (16). In inflamed tissues, C-C motif chemokine ligand 2 (CCL2) is the major chemotactic factor that recruits inflammatory macrophages. In non-inflamed tissues, chemokines and adhesion molecules that recruit and peripheral tissue macrophages and DCs are present constitutively. It has been found that the CXCL14 is related to the structural trafficking of monocytes (17). Moreover, circulating monocytes differentiate into morphologically and phenotypically distinct macrophages. They develop into osteoclasts in bone, microglia in the central nervous system, dust cells in the lung, and Kupffer cells in the liver (Figure 1) (18). Meanwhile, macrophages are highly plastic and can recognize and integrate multiple signals derived from microbes and the diseased tissue environment. Thus, macrophages can be activated at a specific time and place (19). A recent 2025 review emphasized that lung cancer TAMs comprise both monocyte-derived macrophages and tissue-resident macrophages, each with distinct recruitment cues and functional programs (20).

Figure 1 The growth and differentiation of macrophages in yolk sac, fetal liver, bone marrow, and various tissues. Precursor cells in the yolk sac differentiate into mature circulating monocytes in the bone marrow and eventually enter different tissues to differentiate into intratissue macrophages with different roles. CCL2, chemokine ligand 2; CSF-1, colony stimulating factor-1; CSF-1R, colony-stimulating factor 1 receptor; G-CSF, granulocyte stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin.

Macrophage polarization and lung cancer

Macrophages have traditionally been categorized into two activation extremes based on function: classically activated (M1) and alternatively activated (M2) macrophages (M2) (11). The functions of M1 macrophages mainly include bactericidal, proinflammation, immune stimulation, and antitumor activity, while those of M2 macrophages include tissue repair, matrix remodeling, immunosuppression, and protumor activity. The activation factors vary depending on the tumor type, site, and stage, and thus there are different TAM phenotypes (Figure 2) (21). However, TAM phenotypes in lung cancer are being increasingly understood to be a spectrum of activation states rather than discrete M1 or M2 end points: different TAM subsets may preferentially localize to specific tumor niches, display distinct cytokine or chemokine programs, and engage in different immune-cell interaction networks. Moreover, recent single-cell and spatial transcriptomic studies, including analyses in the neoadjuvant setting, suggest that these TAM states can be dynamically remodeled by treatment and are linked to immunosuppression and disease progression (22-25). In summary, macrophages in cancer exert both pro- and antitumor activity depending on the balance between multiple signaling factors (26).

Figure 2 Macrophage polarization and post-polarization effects. M1 and M2 macrophages are polarized into two types under the action of different cytokines. M1 and M2 macrophages exert antitumor and protumor effects, respectively, through the secretion of distinct cytokines; in addition, M1 macrophages exhibit enhanced phagocytic activity. EGF, epidermal growth factor; IFN, interferon; IL, interleukin; MMP, matrix metalloproteinase; NO, nitric oxide; PD-1/PD-L1, programmed cell death protein 1/programmed cell death protein ligand 1; PDGF, platelet-derived growth factor; ROS, reactive oxygen species; TGF, transforming growth factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.

M1 macrophages and lung cancer

M1 macrophages, also known as inflammatory macrophages, are mainly composed of T helper 1 (Th1) cytokines such as IFN-γ and TNF-α and can be activated by bacterial lipopolysaccharide (27). M1 macrophages inhibit the epithelial-mesenchymal transition (EMT) process of tumor cells and reduce their metastatic potential by secreting IFN-γ and TNF-α (28). TNF-α released by M1 macrophages activates caspase-8 to initiate extrinsic and intrinsic apoptotic pathways and generate an antitumor immune responses (29). M1 macrophages can hinder tissue regeneration by mediating reactive oxygen species (ROS)-induced tissue damage and can directly kill tumor cells by releasing nitric oxide and ROS (30), thereby exerting both proinflammatory and antitumor effects (31). Recent evidence in lung cancer further indicates that “M1-like” macrophage programs are not a single, fixed phenotype but rather encompass multiple inflammatory/antigen-presenting states that differ in spatial distribution, immune-cell interaction patterns, and responsiveness to therapy (24,25). M1 macrophages reduce the viability and proliferation of lung cancer cells, enhance their drug sensitivity, and inhibit their tumorigenicity. They can also secrete IL-12 to induce INF-γ production in vivo and in vitro and inhibit the expression of vascular endothelial growth factor, thereby suppressing the angiogenesis induced by lung cancer cells (32,33). Emactuzumab was tested in phase I clinical trials in advanced solid tumors, including lung cancer, and emactuzumab was found to inhibit CSF-1R expression, reduce the abundance of M2-type TAMs, and promote macrophage polarization to the M1 type (34). Accordingly, TAM-modulating strategies targeting the CSF-1-CSF-1R axis are often considered for rational combinations with immunotherapy to enhance antitumor immunity (35,36).

A number of natural compounds exert their tumor-suppressive effects by targeting M1 macrophages but do not do so directly. Rather, they act on different signaling pathways and genes to induce macrophages to M1 polarization (Table 2).

M2 macrophages and lung cancer

M2 macrophages are anti-inflammatory and can activate STAT6 through IL-4 receptor alpha (IL-4Rα). Th2 cells produce the cytokines IL-4 and IL-13, which drives polarization toward the M2 phenotype (31). It is believed that STAT6 is the main pathway involved in M2 macrophage activation (19). M2 macrophages generate four distinct subtypes in response to different stimuli: M2a macrophages promote cell growth and tissue repair, M2b macrophages regulate immune and inflammatory responses, M2c macrophages phagocytose apoptotic cells, and M2d macrophages promote angiogenesis and tumor development (48). Recent lung cancer further indicates that M2-like TAM programs are highly heterogeneous and often occupy distinct tumor niches, with strong immunoregulatory and proangiogenic signatures shaped by the local microenvironment (49). In the tumor microenvironment, M2 macrophages induce tumor cell invasion and progression, leading to poor prognosis in patients with NSCLC. M2 macrophages secrete proteases such as matrix metalloproteinase (MMP)-2 and MMP-9 to degrade the extracellular matrix and create space for tumor cell invasion and migration (50). Single-cell and spatial transcriptomic data in lung adenocarcinoma suggest that M2a-enriched regions are associated with aggressive invasion patterns such as tumor spread through air spaces (STAS), suggesting that M2a-like macrophages possess a spatially organized proinvasive function (51). M2 macrophages can secrete vascular endothelial growth factor (VEGF), promote the proliferation and migration of endothelial cells, and form new blood vessels (33). M2d-like macrophage programs have been reported to secrete VEGF together with immunosuppressive mediators (e.g., IL-10 and CCL18), which links angiogenesis with immune evasion (52). M2 secretes IL-10 and TGF-β, inhibits the activity of T cells and natural killer (NK) cells, and creates an inflammatory environment that promotes tumor growth (53,54).

M2 macrophages can function as a medium, and certain compounds can produce cytokines or cellular pathways to activate this medium to achieve tumor promotion (Table 3). M2a macrophages are activated by IL-4/IL-13 (48). Blockade of STAT-6 phosphorylation induced by IL-4 or IL-13 can prevent the M2 polarization of macrophages and produce antitumor effects (59,63-65,70,72,75,76). M2d macrophages express VEGF induced by catecholamines and promote tumor progression (60).

Metabolic reprogramming of macrophages in lung cancer

Macrophage polarization and function in lung cancer are closely linked to metabolic reprogramming within the tumor microenvironment (79,80). Rather than being determined solely by cytokines or signaling pathways, macrophage states are also shaped by nutrient availability, hypoxia, lactate accumulation, lipid mediators, and other tumor-derived metabolic cues (79,81). In general, proinflammatory M1-like macrophages are more closely associated with glycolytic and ROS-related programs that support rapid immune activation, whereas immunosuppressive M2-like macrophages more often rely on oxidative metabolism, fatty acid utilization, and metabolically adaptive programs that favor tissue remodeling and tumor progression (79). Therefore, metabolism should be regarded as a functional layer of macrophage polarization rather than a parallel phenomenon (79).

In lung cancer, tumor-derived metabolites can directly remodel macrophage behavior (80,81). Lactate-rich conditions in the tumor microenvironment have been associated with M2-like polarization, and recent evidence in lung adenocarcinoma further indicates that enhanced glycolysis and lactate export from tumor cells can reinforce immunosuppressive macrophage programming (58,81,82). Similarly, exosome-associated metabolic regulation provides another link between tumor metabolism and macrophage function (83). For example, macrophage-derived exosomal LINC01001 has been reported to regulate glucose metabolism in lung cancer cells, while tumor-derived exosomes may transfer metabolic enzymes, metabolites, or noncoding RNAs that indirectly reshape macrophage phenotypes (84,85). These findings suggest that metabolic crosstalk is bidirectional: lung cancer cells can metabolically educate macrophages, and macrophage-related metabolic signals can in turn support tumor growth, invasion, and therapy resistance (58,84).

From a functional perspective, metabolic reprogramming helps explain why macrophages in lung cancer often acquire heterogeneous but predominantly protumor features (79,80). Glycolytic stress, lactate accumulation, and lipid-associated signals can promote immune suppression, angiogenesis, extracellular matrix remodeling, and reduced antitumor cytotoxicity, whereas interventions that alleviate oxidative stress or reverse tumor-associated metabolic pressure may facilitate repolarization toward a more antitumor phenotype (39,58,81). Accordingly, targeting macrophage metabolism, including lactate-related pathways, redox imbalance, and other tumor-driven metabolic checkpoints, may represent a promising strategy for remodeling the lung cancer immune microenvironment and improving therapeutic responsiveness (79,81).

Heterogeneity of macrophages in the era of single-cell and spatial transcriptomics

Recent advances in single-cell RNA sequencing and spatial transcriptomics have substantially refined our understanding of macrophage heterogeneity in lung cancer (24,25,86). Rather than representing a simple M1/M2 dichotomy, lung cancer-associated macrophages are now recognized as a spectrum of transcriptionally and functionally distinct states shaped by local tumor niches, treatment exposure, and intercellular communication (87). These technologies have shown that different macrophage subsets may coexist within the same tumor while displaying divergent cytokine programs, antigen-presentation capacity, metabolic features, and immunoregulatory functions (88). Thus, macrophage heterogeneity in lung cancer should be interpreted as a dynamic and spatially organized continuum rather than as two static polarization endpoints (89).

Importantly, single-cell and spatial analyses have revealed that macrophage subpopulations are not randomly distributed, but are preferentially enriched in distinct microenvironmental regions and are associated with different biological roles (86,89). Certain macrophage states are enriched in invasive fronts, hypoxic regions, or immune-excluded niches, where they may promote extracellular matrix remodeling, angiogenesis, immune suppression, and therapy resistance (51). Other subsets show closer spatial association with T-cell-rich regions or display relatively stronger antigen-processing and inflammatory features (88). In addition, treatment-related remodeling has emerged as a major theme: recent studies in NSCLC, including those in the neoadjuvant setting, indicate that macrophage states and their spatial organization can be reshaped after chemoimmunotherapy, with important consequences for immune-cell crosstalk and treatment responsiveness (25).

From a translational perspective, this emerging view of macrophage heterogeneity helps explain why macrophage infiltration alone is often insufficient as a biomarker (90). The clinical significance of macrophages depends not only on abundance but also on subtype composition, spatial localization, and interaction networks with tumor cells and other immune populations (87). Therefore, integrating single-cell and spatial transcriptomic approaches may improve patient stratification, refine prognostic assessment, and facilitate the development of more precise macrophage-targeted combination strategies in lung cancer (25).

Interaction of different exosomes with macrophages in lung cancer

Exosomes are extracellular vesicles that are secreted by almost all cells. Exosomes can transport lipids, proteins, and nucleic acids between cells and organs and play an important role in communication (91). Different proteins, microRNAs (miRNAs), and messenger RNAs (mRNAs) are delivered by exosomes to target cells to alter gene expression (92). The cell type that secretes exosomes determines the function of exosomes (93). Studies have shown that exosomes are absorbed by macrophages to change the phenotype and then promote tumor progression and metastasis in the tumor microenvironment (94). Macrophages can also release exosomes carrying different miRNAs to affect the progression of lung cancer. In addition to miRNAs, TAM- and M2 macrophage-derived exosomes may deliver other RNA cargos such as circular RNAs (circRNAs), which have been implicated in tumor progression and drug resistance (95-97).

Role of macrophage-derived exosomes in lung cancer

Several studies have shown that the exosomes secreted by macrophages act as carriers for transporting miRNAs, long noncoding RNA (lncRNA), and integrins. These substances are involved in the interaction between lung cancer and macrophages and promoting lung cancer to varying degrees (98-100). miRNA is a type of small non–protein-coding RNA. miRNAs can downregulate the expression of target genes, thereby promoting tumor invasion, metastasis, drug resistance, and immunosuppression (101). Lei et al. (102) found that miR-501-3p secreted by M2 macrophages can be transferred to lung cancer cells and promote the proliferation and metastasis of lung cancer by downregulating the level of WD repeat domain 82 (WDR82). Wang et al. (103) demonstrated that exosomes produced by M2 macrophages deliver miR-3679-5p, which is involved in the signaling cascade of chemoresistance in lung cancer. Peng et al. (104) examined the transport of miR-let-7b-5p by exosomes produced by M1 macrophages. The found that miR-let-7b-5p can downregulate GNG5 protein in tumor cells and inhibit the proliferation and metastasis of lung cancer cells. In addition to miRNAs and lncRNAs, macrophage-/TAM-derived exosomes can also shuttle circRNAs, which may rewire oncogenic signaling and contribute to targeted-therapy resistance in patients with NSCLC (105). LncRNAs are noncoding RNAs over 200 nt in length. Studies have shown that they figure prominently in the occurrence and development of malignant tumors (106-108). Xu et al. (84) demonstrated that LINC01001, an exosome derived from M2 macrophages, can regulate glucose metabolism in lung cancer cells to promote tumor development. In addition, recent evidence indicates that M2 macrophage-/TAM-derived exosomal lncRNAs can modulate radiotherapy response, suggesting a broader role of macrophage exosomal cargos in treatment resistance (109). Integrins are transmembrane receptors that mediate cell-cell signaling and contribute to tumor cell metastasis and immune escape (110,111). Huang et al. found that exosomes derived from M2-like macrophages can transfer αVβ3 NSCLC cells and activate the focal adhesion enzyme signaling pathway, thereby promoting NSCLC migration (112). Exosomal integrins are being increasingly recognized as functional mediators of tumor-stroma communication and as therapeutic targets, and this has added to the clarification of the mechanistic framework for integrin-cargo-driven metastasis and immune evasion (113).

Role of lung cancer-derived exosomes in lung cancer

Tumor cell-derived exosomes can regulate tumorigenesis, growth, invasion, and metastasis. These exosomes affect macrophages through different genetic and cellular pathways to produce pro- or antitumor effects (114,115). Recent reviews have further established that lung cancer-derived exosomal cargos include not only miRNAs but also circRNAs and proteins, which can converge on inflammatory/immune signaling (e.g., JAK/STAT and NF-κB) to reshape macrophage polarization and immunosuppression (116). Different miRNAs secreted by lung cancer cells promote M2 polarization by upregulating gene expression and activating signaling pathways, thereby promoting tumor invasion and metastasis. Chen et al. (66) confirmed that miR-19b-3p in the exosomes of lung adenocarcinoma cells inhibit STAT3 dephosphorylation in macrophages leading to M2 polarization. Ma et al. (117) demonstrated that miR-181b in exosomes derived from NSCLC cells promote M2 polarization by regulating the JAK2-STAT3 axis. Xu et al. (118) reported that miR-19b-3p in exosomes from lung adenocarcinoma cells can also promote M2 polarization through the JNK signaling pathway. In addition, emerging evidence indicates that exosomal circRNAs from NSCLC can also drive M2 polarization through miRNA-mRNA axes, providing another layer of posttranscriptional regulation beyond miRNAs alone (119). Fabbri et al. (120) reported that miR-21 and miR-29a in lung cancer exosomes activate the NF-κB pathway through TLR8 to induce macrophage polarization to the M1 phenotype. Jin et al. (121) found that lung cancer–derived exosomes carrying high miR-21 levels in the hypoxic environment promote the M2 polarization of macrophages and induce lung cancer progression by targeting IRF1. Moreover, tumor cell-derived LINC00313 in exosomes upregulates STAT6 expression to promote M2 polarization, ultimately promoting tumor development (61). Notably, tumor exosomes have been known to exert context-dependent effects on macrophage polarization (e.g., hypoxia and specific cargo composition), which may partially explain the coexistence of both M1- and M2-polarizing signals reported across studies (83). In contrast, tumor-derived exosomes also have antitumor effects. Liu et al. (122) found that NSCLC-derived exosomes carrying miR-770 downregulate the MAP3K1 gene to inhibit M2 macrophage polarization, resulting in an inhibitory effect on lung cancer growth and invasion.

Taken together, macrophage-derived and lung cancer-derived exosomes show substantial functional overlap, as both types of extracellular vesicles can shuttle bioactive cargos such as miRNAs, lncRNAs, circRNAs, proteins, and integrin-related signals to reshape intercellular communication within the tumor microenvironment. In both settings, exosomal signaling contributes to tumor progression, metastasis, immune suppression, and therapeutic resistance. However, there are also important differences between these two sources of vesicles. Macrophage-derived exosomes more often act as downstream effectors of macrophage functional states and directly influence lung cancer cell behavior, including proliferation, migration, metabolism, and drug response, whereas lung cancer-derived exosomes more often act as upstream education signals that reprogram macrophages and remodel their polarization state. In particular, tumor-derived exosomes frequently promote M2-like polarization through STAT3, JAK/STAT, NF-κB, and related signaling axes, thereby reinforcing an immunosuppressive microenvironment, although context-dependent M1-polarizing effects have also been reported. By contrast, macrophage-derived exosomes reflect the heterogeneity of macrophage populations themselves: exosomes released from M2-like macrophages or TAMs are generally protumor, whereas those derived from M1-like macrophages may exert antitumor effects. Therefore, the biological significance of extracellular vesicles in lung cancer should be interpreted not only according to their cargo composition but also according to their cellular origin, because these two factors jointly determine their influence on macrophage polarization and tumor progression (96,123,124).

Interaction of inflammatory factors and macrophages in lung cancer

Role of inflammatory factors produced by macrophages in lung cancer

Macrophages are capable of secreting different inflammatory factors. These inflammatory factors are an important part of the tumor microenvironment, and their role may be dual, in that they both help fight tumor cells and promote tumor invasion and metastasis (125). IL-6 and TGF-α are the primary factors that promote the growth and metastasis of lung cancer cells (126,127). TAMs activate the STAT3 signaling pathway by secreting IL-6, thereby promoting the proliferation and progression of SCLC cells (128). Mechanistic and multiomics studies in lung cancer further indicate that TAM-derived IL-6 can serve as a hub cytokine linking inflammatory signaling to tumor progression. IL-6/STAT3 signaling not only sustains tumor-cell survival but can also drive EMT-associated transcriptional programs, thereby facilitating invasion and dissemination (20,129). Certain substances, such as cytoplasmic phospholipase A2, can enhance the induction of IL-6 in the coculture of cancer cells and macrophages, as well as promote the development of cancer by affecting the tumor cells or stroma (130). Moreover, macrophages can induce EMT by secreting inflammatory factors such as IL-6, thus playing a role in promoting the invasion of lung cancer cells. M2 macrophages play a particularly prominent role in this process (130,131). In NSCLC, IL-6- and STAT3-driven EMT has been connected to certain downstream mediators (e.g., FGL1) that couple metastatic potential with immune suppression, and this phenomenon offers a more “molecularly specified” explanation for cytokine-driven invasion (129). TNF can stimulate tumor cells to produce VEGF, which contributes to tumor growth. In addition, TNF activates tumor cells to produce immunosuppressive factors such as TGF-β and IL-10, which in turn help tumor cells become "invisible" from the immune system (132). This TNF-centered loop is being increasingly examined in conjunction with canonical immune-evasion circuits (e.g., checkpoint signaling and cytokine-mediated suppression) and may explain how inflammatory cytokines can simultaneously accelerate angiogenesis and blunt antitumor immunity (133). TNF-α secreted by macrophages can induce mutations and affect EMT and subsequent cancer cell invasion (134). TGF-β promotes lung cancer growth and immune escape by inducing IRAK-M expression in TAMs (135). Work focusing on the TGF-β axis in lung cancer further highlights its dual impact on tumor cells and myeloid compartments, and the IRAK signaling node (including IRAK-M) has been repeatedly identified as a part of the myeloid-associated immunosuppressive mechanism and a potential intervention point (136-138).

Effects of tumor cell-produced inflammatory factors

The inflammatory cells and cytokines produced by malignant tumors can alter the tumor microenvironment, and inflammatory factors interact with tumors in the process of angiogenesis, tumor growth, migration, and chemotherapy resistance (139). The angiogenic factor VEGF produced by macrophages is an important protumor angiogenic component (140). Studies have shown that the expression of IL-1β in lung cancer cells increases after coculture with M2-type TAMs, which promotes angiogenesis and accelerated tumor growth (141). Importantly, tumor-cell IL-1β can also act as a “treatment-context” cytokine. Specifically, a translational study in NSCLC reported that cancer cell-derived IL-1β reshapes the immunosuppressed microenvironment and can reverse resistance to chemoimmunotherapy, suggesting that tumor-derived inflammatory cues may have context-dependent effects rather than being uniformly tumor-promoting (142). IL-34 produced by cancer cells promotes chemotherapy resistance by activating AKT pathway and inhibits immunity by acting upon macrophages to promote tumor (143). Consistent with the functional relevance of the IL-34-CSF-1R axis, therapeutic “trapping” of CSF-1 and IL-34 has been shown to reduce suppressive TAMs in vivo, supporting the notion that IL-34 is not merely a biomarker but also a druggable upstream driver of macrophage-mediated immunosuppression (144). It has also been shown that cytoplasmic phospholipase A2 (cPLA2) from bone marrow–derived macrophages promotes IL-6 production by cancer cells and contributes to tumor progression and angiogenesis (130). IL-1α produced by cancer cells can induce potent inflammatory stimuli to activate M2 macrophages, support tumor lymphangiogenesis and angiogenesis, and promote the extensive metastasis of lung cancer (145). The synthesis of epidemiologic and clinical data has linked IL-1 family signals with angiogenesis and lymphangiogenesis in lung tumor tissues, providing a clinical explanation for IL-1α-/IL-1β-driven prometastatic remodeling (146). Tumor-derived M-CSF can induce the polarization of CD14⁺CD163⁺ M2 macrophages and further promote the metastasis and angiogenesis of NSCLC (147).

Interaction between inflammatory factors in the lung cancer microenvironment

Inflammatory cytokines, such as IL-17, IL-9, TNFSF15, and IFN-γ, are produced by different cells in the tumor microenvironment. They play a variety of roles in the interaction between macrophages and lung cancer. IL-17 promotes the growth of lung cancer cells by activating the NF-κB pathway to polarize macrophages to the M2 type (148,149). Moreover, macrophages can be aggregated by IL-17 and induced to differentiate into M2-macrophages by PGE2 (150). A mechanistic link between IL-17 and the premetastatic niche has been established for the metastasis of NSCLC. Specifically, tumor-associated IL-17 recruits macrophages and promotes a PGE2-rich milieu that biases macrophage polarization toward an M2-like state, thereby facilitating metastatic outgrowth (151). IL-9 from CD4⁺ T cells promotes the growth of the macrophage population and promotes tumor progression through arginase 1 (Arg1) (152). TNFSF15 activates STAT1/3 but inactivates STAT6, leading to the transformation of the M2 into M1 phenotype, and contributes to tumor suppression (43). Clinical-oriented analyses of NSCLC TAM biology have also identified the Th17-/IL-17A-associated induction of M2 TAM polarization and, conversely and confirmed that the TNFSF15-mediated inhibition of STAT6 acts as a switch favoring M1-like polarization (153). Interferon and Toll-like receptor ligands synergistically stimulate M1 polarization to produce antitumor effects (154,155). In translational immunotherapy, type I interferon combined with TLR3 ligands has been used as a chemokine-modulatory regimen to reprogram stromal/myeloid compartments and enhance cytotoxic T lymphocyte-attracting chemokines, providing a practical framework for leveraging IFN-TLR synergy in “cold” tumors (156).

Interactions between macrophages and other immune cells in lung cancer

Macrophages do not function in isolation in the lung cancer microenvironment but instead engage in extensive crosstalk with multiple immune-cell populations, including T cells, DCs, myeloid-derived suppressor cells (MDSCs), and neutrophils, as well as natural killer (NK) cells (157). These bidirectional interactions influence antigen presentation, immune-cell recruitment, cytokine and chemokine gradients, and the balance between antitumor immunity and durable immune suppression (158). Therefore, macrophage-centered immune regulation in lung cancer should be understood as a multicellular network rather than a single-cell process (159).

Macrophage-T cell interactions

In the growing tumor, macrophages exert regulatory effects on T cells, NK cells, and other immune cells, and their interactions can affect tumor progression. M1-like macrophages are initially activated, and they recruit CD8⁺ T cells and NK cells by releasing chemokines and cytokines, leading to the formation of an inducible immune system (160). Spatially resolved profiling of NSCLC has further mapped macrophage-T cell neighborhoods and immune-cell network organization, which indicates that macrophage localization and contact patterns shape T-cell states within distinct tumor niches (88). Macrophag-T cell crosstalk is therefore one of the most functionally important immune interactions in lung cancer. In an immune-supportive context, macrophages with inflammatory or antigen-presenting programs can recruit and sustain cytotoxic T-cell responses through chemokine secretion and local immune activation. In contrast, immunosuppressive TAMs can restrict T-cell infiltration, attenuate antigen presentation, and reinforce T-cell dysfunction through inhibitory cytokines, checkpoint-related signaling, and stromal remodeling (36).

Some studies have found that PD-L1 expressed on tumor cells binds to the PD-1 receptor on T cells, leading to T-cell-negative regulation and immune escape in tumors. The basic mechanism of PD-1/PD-L1 blockade immunotherapy involves restoration of T cell’s ability to recognize tumors and initiate immunotherapy by blocking the PD1 receptor or PD-L1 ligand (161-163). Mechanistic analyses have also indicated that PD-1/PD-L1 signaling is orchestrated by both tumor and immune compartments (including antigen-presenting cells), which helps to explain the heterogeneous responses to checkpoint blockade (164). In addition, macrophages themselves can contribute to the efficacy or resistance of PD-1/PD-L1 inhibitors by regulating T-cell trafficking, exhaustion status, and local checkpoint ligand expression. Thus, macrophages influence not only whether T cells infiltrate the tumor bed, but also whether they maintain effective cytotoxicity and respond to immune checkpoint blockade (160).

Mechanistically, this influence is exerted through multiple routes. One important mechanism is that TAMs may restrict the infiltration of cytotoxic T cells into tumor nests and maintain an immunosuppressive microenvironment, thereby limiting the reinvigoration of antitumor T-cell responses after checkpoint blockade. Moreover, macrophages can shape the local response to PD-1/PD-L1 inhibitors through the production of inhibitory cytokines, modulation of antigen-presentation programs, and coordination of suppressive signaling networks within the tumor microenvironment (165).

Accumulating evidence suggests that the impact of macrophages on PD-1/PD-L1 blockade is context-dependent but is frequently associated with resistance when macrophages adopt predominantly M2-like or suppressive states. In this setting, macrophage-rich immune-excluded niches may blunt T-cell access to tumor cells and reduce the effectiveness of checkpoint inhibition (160). By contrast, strategies that deplete suppressive TAMs or reprogram macrophages toward a more inflammatory phenotype may enhance the response to PD-1/PD-L1 inhibitors. Therefore, macrophages should be viewed not only as participants in checkpoint-related signaling, but also as key determinants of sensitivity or resistance to PD-1/PD-L1 blockade in lung cancer (166).

Macrophage-DC interactions

Macrophage-DC interactions constitute another important layer of immune regulation in lung cancer. Although both macrophages and DCs belong to the myeloid compartment, they play partially distinct roles in antigen uptake, antigen presentation, and T-cell priming (167). Under immune-active conditions, these two cell populations may cooperate to support antigen processing and local antitumor immunity (168). However, in the immunosuppressive tumor microenvironment, TAM-associated cytokines and suppressive mediators can impair DC maturation, limit effective antigen presentation, and thereby weaken downstream T-cell activation. Lung tumor-infiltrating DCs themselves may also be functionally reprogrammed by the tumor microenvironment toward tumor-supporting phenotypes, indicating that macrophage-mediated immune suppression may extend indirectly through DC dysfunction (167,169).

From a therapeutic perspective, the growing interest in DC-based immunotherapy for non-small cell lung cancer also highlights that macrophage-DC crosstalk may be highly relevant to restoring productive antitumor immunity in immunologically suppressed tumors (170).

Macrophage-myeloid-derived suppressor cell interactions

Macrophages also interact closely with myeloid-derived suppressor cells (MDSCs), which are another major immunosuppressive myeloid population in lung cancer (158,171). TAMs and MDSCs often coexist within the same tumor microenvironment and may reinforce one another through overlapping cytokine networks, growth factors, and inflammatory mediators (172). This functional cooperation can amplify T-cell suppression, promote tumor immune tolerance, and sustain a protumor inflammatory state (158). Rather than acting as isolated suppressor populations, TAMs and MDSCs should be viewed as coordinated components of a broader myeloid immunoregulatory system. This perspective is important because it suggests that therapies targeting only one suppressive myeloid population may be insufficient and that combined myeloid reprogramming strategies may be more effective (171).

Macrophage interactions with neutrophils and NK cells

Macrophages further shape innate immune responses through their interactions with neutrophils and NK cells (49,173). Crosstalk between macrophages and neutrophils may influence inflammatory amplification, extracellular matrix remodeling, and metastatic niche formation, thereby contributing to lung cancer progression in a context-dependent manner (174-176). Recent reviews of lung cancer have highlighted that tumor-associated neutrophils interact dynamically with other immune cells through cytokines, chemokines, neutrophil extracellular traps, and extracellular vesicles, suggesting that macrophage-neutrophil cooperation may represent an additional axis of immunosuppressive and prometastatic regulation (174,177,178).

TREM2⁺ mononuclear macrophages reduce NK cell activity by regulating IL-18/IL-18BP decoy interaction and IL-15 production (179). TREM2 blockade acts synergistically with NK cell activators to further inhibit tumor growth (180). These findings indicate that macrophages regulate not only adaptive immunity but also innate immune cytotoxicity, further supporting the concept that macrophage reprogramming may enhance antitumor responses across multiple immune compartments (179,181).

In addition, M1 and M2 macrophages have been shown to be co-expressed in early lung tumors, a condition in which the inhibitory effect of T cells is greater (173,182). Macrophage-targeted immunomodulatory strategies that leverage myeloid-T cell-NK cell synergy have also been explored and may provide an experimental basis for therapeutically reshaping these intercellular circuits (183). Taken together, macrophage interactions with T cells, DCs, MDSCs, neutrophils, and NK cells indicate that macrophages serve as immune coordinators rather than merely effector cells in lung cancer. These multicellular interactions help determine whether the tumor microenvironment evolves toward immune activation or durable immune suppression. Accordingly, future macrophage-targeted strategies should be evaluated not only in terms of macrophage polarization alone but also in relation to their broader effects on the immune-cell network (173,184).

Macrophages and canonical pathways in lung cancer

The interaction between lung cancer cells and macrophages often plays a dual role in promoting antitumor effects through the abnormal activation or inactivation of a variety of cell signal transduction pathways. Therefore, these pathways are the bridge between lung cancer and macrophages. Studies have shown that macrophages are involved in a number of signaling pathways relevant in lung cancer, such as the NF-ƘB pathway, STAT3 pathway, STAT6 pathway, and PI3K/AKT/mTOR pathway. The interactions between macrophages and four pathways in lung cancer are summarized in Figure 3.

Figure 3 Pathways between macrophages and lung cancer cells. The interaction between macrophages and lung cancer depends on the signal transmission mediated by cytokines and exosomes. IL-6, miR-181b, IL-4/IL-13, and LINC00313 released by tumor cells activate JAK2-STAT3 pathway and STAT6 pathway in macrophages, respectively. Moreover, tumor-promoting cytokines including miR-3679-5p, IFN-γ, and LINC01001 are secreted from macrophages and bind to their corresponding receptors on the surface of lung cancer cells to induce PI3K, Akt, and NF-κB responses, promoting lung cancer. miR-501-3P promotes the proliferation of lung cancer cells by silencing WD repeat domain 82. Integrin αVβ produced by macrophages activates the adhesion enzyme pathway to promote tumor metastasis. In addition, JNK and KDM6B are also key links in the interaction between macrophages and lung cancer cells, affecting the polarization of macrophages. In vivo, IL-17 also promotes lung cancer by acting on the NF-KB pathway in lung cancer cells. IL, interleukin; IFN-γ, interferon-γ; JAK2, Janus kinase 2; STAT3, signal transducer and activator of transcription 3; STAT6, signal transducer and activator of transcription 6; KDM6B, lysine demethylase 6B; JNK, c-Jun N-terminal kinase; miR, microRNA; LINC, long intergenic non-protein coding RNA; PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; NF-κB, nuclear factor kappa-B; PP2AC, protein phosphatase 2A catalytic subunit; CCL2, C-C motif chemokine ligand 2; CCL7, C-C motif chemokine ligand 7; WDR82, WD repeat domain 82; Nedd4, neural precursor cell expressed developmentally downregulated 4; C-Myc, MYC proto-oncogene, bHLH transcription factor; αVβ3, integrin αVβ3.

NF-κB signaling pathway

The components of the NF-κB pathway, such as p65, p50, and Rel-B, can form dimers that enter the nucleus, bind to the κB enhancer on target genes, and enhance the transcription of target genes (185). IL-17 increases the nuclear localization of p65 (a subunit of NF-κB) and activates NF-κB in macrophages, thereby promoting the polarization of macrophages into M2 and promoting lung cancer (148). CCL2 has been identified as one of the classical target genes of NF-κB (186). The neddylation pathway activates the NF-ƘB signaling pathway by enhancing CCL2 gene expression, thereby producing the biological effect of promoting lung cancer (187). PP2Ac is a gene with potential biological functions in NSCLC cells. The pro-lung cancer effect of macrophages in the tumor microenvironment is achieved through the downregulation of PP2Ac expression through the NF-κB/PP 2Ac feedback mechanism (188). Macrophages in tumor tissue secrete resistin. PI3K/NF-κB is a key factor in the downstream signaling pathway in tumor cells, and resistin promotes tumor cell metastasis through PI3K/Akt/NF-κB signaling factors (189). Lung cancer cells secrete cytokines such as IL-6 and TNF-α to activate NF-κB, and TAMs upregulate the expression of TGF-β. TGF-β can inhibit the activity of T cells and NK cells, as well as promote the M2-type polarization of TAMs (190). TAMs can activate the NF-κB pathway and induce the expression of IL-6 in lung cancer cells by secreting cytokines such as IL-10 and TGF-β. IL-6 further promotes tumor cell proliferation and survival through the JAK/STAT3 pathway (191). Moreover, TAMs can activate the NF-κB pathway in lung cancer cells by secreting VEGF, MMPs and other factors, and promote angiogenesis and metastasis (192).

STAT3/STAT6 signaling pathway

The STAT protein family is involved in the regulation of cell proliferation, differentiation, angiogenesis, and other physiological processes. In particular, STAT3 and STAT6 play important roles in lung cancer (193). A number of growth factors and cytokines are transmitted through the JAK/STAT pathway. IL-6 activates STAT3 and can directly promote the production and metastasis of tumor cells. Therefore, the role of IL-6/JAK/STAT3 pathway is closely related to the promotion of tumor development (194,195). Previous studies have shown that the IL-6 produced by lung cancer cells is involved in the activation of JAK/STAT3 pathway and plays a role in promoting lung cancer proliferation (128,196). TAMs activated by STAT3 promote tumor cell survival, proliferation, and angiogenesis by secreting growth factors such as VEGF, EGF, and FGF (197). STAT3 inhibits the expression of antigen presentation and costimulatory molecules in TAMs, thereby weakening T cell-mediated antitumor immune responses (198). Mechanistic synthesis in lung cancer further indicates that IL-10-STAT3 signaling in antigen-presenting cells can downregulate MHC and costimulatory programs, providing a more explicit link between STAT3 activity and impaired T-cell priming (49). Meanwhile, the synergistic effect of STAT3 and NF-κB can enhance the expression of IL-10 and IL-6, induce M2 polarization, and further promote immunosuppression and tumor growth (199). Some studies have found that macrophages in the tumor microenvironment secrete IFN-γ through the JAK/STAT3 pathway. IFN-γ promotes the development of lung cancer through the PI3K/AKT pathway (200). In 2010, it was first reported that the high expression of STAT6 is associated with the poor prognosis of patients with tumors (201). Other findings have demonstrated that both IL-4 and IL-13 can induce STAT6 phosphorylation. STAT6 is a key player in the M2 polarization of macrophages (202). In lung cancer cells, gefitinib reduce STAT6 phosphorylation by inhibiting IL-13 via the above-described mechanism and ultimately inhibits lung cancer (64). TNF-associated factor 3 (TRAF3) enhances IL-4-induced macrophage polarization by promoting STAT6 ubiquitination, which can promote tumor growth and lung metastasis in vivo (203). In line with the ubiquitin-dependent control of STAT6 activity, USP25-mediated deubiquitination can stabilize STAT6 and enhance IL-4-driven M2 polarization (204). STAT6 phosphorylation can upregulate M2-related genes (such as Arg1, Ym1, and Fizz1) and induce the expression of IL-10 and TGF-β in TAMs, thereby inhibiting the function of T cells and NK cells. Following STAT6 activation, TAMs promote the expression of VEGF and MMPs, supporting tumor angiogenesis and invasion (205,206).

PI3K signaling pathway

The PI3K signaling pathway is activated by a variety of cytokines in cells. PI3K signaling pathway influences the polarization of macrophages. As a downstream mediator of PI3K, AKT is also involved in the regulation of cell proliferation and migration (207). Yuan et al. (208) reported that macrophages in the tumor microenvironment activate the PI3K/AKT signaling pathway, thereby promoting the progression of lung cancer. Moreover, Zhang et al. (200) found that IFN-γ produced by macrophages in lung cancer enhances PD-L1 expression and activates the PI3K/AKT signaling pathway, leading to a tumor-promoting effect. PI3K signaling pathway can also be connected with EGFR pathway and NF-κB pathway in tandem (189). Kaneda et al. (209) demonstrated that PI3Kγ inhibition can reverse the M2-type polarization of TAMs and enhance antitumor immune response. Consistent with this concept, PI3Kγ has been highlighted as a myeloid-intrinsic node that sustains immunosuppressive programs in the tumor microenvironment, a fact which supports PI3Kγ inhibition as a macrophage-reprogramming strategy (210). De Henau et al. (211) found that the inhibition of the PI3K pathway could downregulate the expression of immunosuppressive molecules (such as IL-10, TGF-β, and ARG1) and enhance the activity of T cells and NK cells, thereby improving the efficacy of immune checkpoint inhibitors (such as PD-1/PD-L1 inhibitors). In lung cancer models, in situ TAM reprogramming approaches incorporating PI3Kγ-related targets have been examined in terms of their ability to enhance antitumor immunity in order to generate a practical delivery-oriented framework for combining PI3K modulation with immunotherapy (212). Moreover, Glaviano et al. (213) reported that PI3K inhibition can reduce VEGF expression and inhibit tumor angiogenesis, thereby enhancing the efficacy of chemotherapy and radiotherapy.

Macrophage- and gene-related mechanisms in lung cancer

Macrophages secrete cytokines such as IL-2, interferon, and granzyme to induce the apoptosis or death of tumor cells. However, tumor cells evade immune recognition or killing by reducing their own surface antigens, gene mutations, and other mechanisms, thus establishing immune tolerance. Different gene expressions exert various biological effects. The upregulation or downregulation of genes can affect the interaction between macrophages and lung cancer. Studies have shown that some anticancer drugs can exert antitumor effects by targeting specific genes (214,215). The mechanisms underlying the gene-related interaction between macrophages and lung cancer are summarized in Table 4.

Clinical and prognostic implications of macrophages in lung cancer

The role of macrophages in the tumor microenvironment of lung cancer is complex and variable, and thus different macrophage types exert varying effects on the treatment and prognosis of patients with lung cancer. Research indicates that both M1 and M2 macrophages are infiltrated in the islets of NSCLC, and the tumor islets of patients with a prolonged survival are mostly infiltrated by cytotoxic M1 macrophages (227). Therefore, the density of M1 macrophages in tumor islets can be used to predict the survival time of patients with NSCLC (228). In contrast, M2 macrophages can induce the proliferation and invasion of tumor cells and promote tumor progression and metastasis. Previous studies have shown that M2 macrophage-infiltrated tumor islets contribute to a poor prognosis among patients with NSCLC (229,230). Moreover, integrative analyses suggest that M2-polarized TAMs are closely associated with angiogenesis and lymphangiogenesis in NSCLC, and that the combination of a high intratumoral M2/M1 macrophage ratio and elevated VEGF-C expression provides superior prognostic stratification compared with single biomarkers (231). In addition, the different antibodies expressed by macrophages have varying degrees of correlation with the clinical stage and prognosis of patients with lung cancer. CD204⁺ TAMs can contribute to the formation of a tumor-promoting microenvironment and have been associated with prognosis in patients with lung squamous cell carcinoma (232). CD68⁺ macrophages expressing B7-H4 have also been linked to tumor progression (233), while CD68⁺ and CD204⁺ macrophages in the intratumoral stroma have been reported to predict NSCLC prognosis, with CD204⁺ macrophages being proposed to be a candidate prognostic marker (233). Spatially resolved profiling of lung tumor immune microenvironments further suggests that macrophage location and neighborhood context are key determinants of their clinical impact, a finding which has reconciled heterogeneous findings across cohorts (89).

PD-L1 is expressed in both macrophages and lung cancer cells, which affects the treatment and prognosis of lung cancer to varying degrees. Gross et al. (234) found that patients with high PD-L1 expression on macrophages or lung cancer cells received a significant survival benefit from adjuvant chemotherapy. Liu et al. (235) analyzed 500 patients with NSCLC and found that PD-L1 expression was upregulated on CD68⁺ macrophages, a condition which was associated with better OS. In addition, soluble PD-L1 (sPD-L1), which may arise from cleavage or shedding of membrane-bound PD-L1 on tumor cells, can be detected in the peripheral blood. Other studies have shown that patients with higher preoperative sPD-L1 levels in plasma and high PD-L1 expression intensity in tumor cells have a higher probability of 5-year recurrence-free survival than those with low expression intensity. Preoperative measurement of plasma PD-L1 level and PD-L1 expression in tumor cells and TAMs can be used to evaluate the prognosis of NSCLC (236).

Discussion and prospects

Macrophages play a crucial role in the lung cancer tumor microenvironment, and their functions are shaped by diversity cytokines, exosomal communication, and interconnected signaling pathways. This paper provides a review of the role of macrophages in lung cancer, including in relation to polarization, exosomes, cytokines, canonical pathways, and gene-associated mechanisms; examines their clinical and prognostic implications; and summarizes the compounds and cytokines that utilize M1/M2 polarization to produce pro- or antitumor effects.

At the functional level, macrophages can restrain malignant behaviors when polarized toward M1-like programs by reducing the viability and proliferation of lung cancer cells, enhancing drug sensitivity, inhibiting tumorigenicity, and limiting tumor-driven angiogenesis. Conversely, M2-like macrophages promote tumor cell growth, invasion, and metastasis, which are frequently associated with poor prognosis in patients NSCLC. Importantly, these effects are not solely dictated by a binary M1/M2 classification; rather, macrophage programs can be reshaped by microenvironmental cues (e.g., hypoxia, inflammatory cytokines, and metabolic stress) and by bidirectional communication with tumor cells and other immune populations. It should also be acknowledged that the classical M1/M2 dichotomy, although still useful as a conceptual framework, is an oversimplification of macrophage biology in vivo. In lung cancer, many macrophages exhibit mixed, intermediate, or transitional phenotypes rather than fitting neatly into two mutually exclusive categories. Their functional states are shaped by spatial location, metabolic conditions, cytokine exposure, treatment history, and interactions with tumor cells and other immune populations. Therefore, binary classification may be insufficient to capture the full complexity of macrophage behavior in the lung cancer microenvironment. A more realistic interpretation is that macrophage states exist along a dynamic continuum, and this view is increasingly supported by single-cell and spatial transcriptomic studies. Recognizing the limitations of the M1/M2 model is important not only for mechanistic understanding but also for the development of more precise macrophage-targeted therapeutic strategies (25).

Exosomes produced by macrophages or tumor cells represent a key layer of this bidirectional communication. Beyond the general concept that exosomes transport lipids, proteins, and nucleic acids, it is understood that certain cargos have functional relevance in lung cancer. For instance, tumor-derived exosomal miRNAs (e.g., miR-19b-3p and miR-181b) can polarize macrophages toward an M2-like state through STAT3-related axes, while macrophage-derived exosomes can also directly rewire tumor cell behavior (e.g., M2-like macrophage exosomal αVβ3 promoting NSCLC migration and M1-like macrophage exosomal miR-let-7b-5p suppressing tumor proliferation and metastasis) (66,104,112). Therefore, after the molecular mechanisms by which exosomal cargos influence the malignant process of lung cancer are clarified, exosome-based readouts may become useful biomarkers for diagnosis and risk stratification, while exosome-related pathways may provide therapeutic entry points.

The occurrence, development, invasion, and metastasis of lung cancer are closely related to multiple signaling pathways, and macrophage-tumor crosstalk converges on a limited set of canonical axes (e.g., NF-κB, JAK/STAT3-STAT6, and PI3K/AKT/mTOR). Achieving the means to modulating these pathways to better inhibit lung cancer progression remains a major therapeutic challenge. Metastasis-related pathway networks and their feedback loops should be more intensively investigated, as identifying actionable nodes within these networks may offer tractable targets to prevent dissemination. Notably, the regulation of macrophage polarization itself is multilayered: in addition to phosphorylation-based activation, ubiquitin-dependent control of STAT6 has emerged as an additional regulatory layer, and deubiquitination (e.g., USP25-mediated stabilization of STAT6) (204) can amplify IL-4-driven M2 polarization, indicating that “state control” may occur at multiple posttranslational checkpoints.

Macrophages not only act on tumor cells but also regulate other immune cells in the tumor microenvironment, thereby participating in immune microenvironment remodeling. This broader immune orchestration may contribute to treatment failure when macrophage programs enforce immune suppression. Studies have shown that macrophages in the tumor microenvironment of lung cancer can express both PD-1 and PD-L1 (161). Moreover, in addition to regulating the polarization state of macrophages, macrophage-targeted therapy can improve the efficacy of immune checkpoint inhibitors (160), which constitutes a rationale for implementing combination regimens. It is also worth noting that the prognostic and predictive value of PD-L1 can differ by cellular compartment. Specifically, PD-L1 expression on macrophages and on tumor cells may show distinct, and sometimes even opposite, associations with clinical outcomes across different cohorts and treatment contexts, indicating that PD-L1 should not be interpreted as a uniform biomarker but rather in relation to cell type, spatial location, and therapeutic setting. Several upstream determinants of macrophage states remain incompletely defined in lung cancer. ROS can drive macrophage activation and function, which prompts the question as to whether ROS-related mechanisms directly participate in TAM-mediated tumor regulation (237). In addition, whether metabolomic remodeling and biological rhythms influence TAM function and treatment responsiveness warrants further investigation. Overall, the mechanistic map of lung cancer–associated macrophages is still evolving, and more clinically anchored experimental studies are needed to clarify the causal relationship between macrophage state transitions and therapy response and resistance.

Developing novel drugs and therapeutic approaches that modulate macrophage activity and function will likely remain a major focus of future research. In this regard, there are two priorities: (I) patient stratification—identifying which immune contexts are most likely to benefit from TAM reprogramming—and (II) regimen design—optimizing the timing and sequencing of regimens that combine TAM-targeted therapy with immunotherapy, radiotherapy, or chemotherapy. In parallel, an improved understanding of macrophage interactions with T cells and NK cells may allow for a more rational development of combination strategies. For example, TREM2⁺ macrophage programs can suppress NK activity via IL-18/IL-18BP- and IL-15-related mechanisms, suggesting that “myeloid-NK” circuitry may represent an additional lever beyond T-cell-centric paradigms. Overall, integrating mechanistic studies, spatial/single-cell profiling, and well-designed clinical investigations may lead to breakthroughs in macrophage-centered lung cancer therapy.

Conclusions

Macrophages are key regulators of the lung cancer tumor microenvironment and influence tumor progression, immune evasion, treatment response, and prognosis through polarization, exosome-mediated communication, inflammatory cytokines, canonical signaling pathways, and gene-related mechanisms. Although the M1/M2 framework remains useful, macrophage states in lung cancer are highly heterogeneous and dynamically shaped by spatial, metabolic, and immune-contextual factors. Targeting macrophage polarization and macrophage-related signaling networks may provide promising opportunities for improving prognostic assessment and therapeutic efficacy in lung cancer.

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-2026-0418/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0418/prf

Funding: This study was funded by the Shandong Natural Science Foundation (Nos. ZR2021LSW023, ZR2022MH111, ZR2021QH356, and ZR2022MH103) and the Shandong Province Medicine and Health Science and Technology Development Plan Project (No. 202009031334).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0418/coif). All authors report that this study was funded by the Shandong Natural Science Foundation (Nos. ZR2021LSW023, ZR2022MH111, ZR2021QH356, and ZR2022MH103) and the Shandong Province Medicine and Health Science and Technology Development Plan Project (No. 202009031334). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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(English Language Editor: J. Gray)