Understanding the dual role of granulocyte-macrophage colony-stimulating factor in the lung cancer tumor microenvironment and its therapeutic implications

Introduction

Lung cancer is the malignancy with the highest global mortality, accounting for over 1.8 million deaths annually (1). The World Health Organization (WHO) classifies lung cancer into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). NSCLC constitutes 80–85% of all lung cancer cases, while SCLC accounts for 15% (2-4). Although immune checkpoint inhibitors (ICIs) have revolutionized lung cancer treatment over the past decades, a significant proportion of patients still fail to derive clinical benefit from ICIs (5). The core of this therapeutic dilemma lies in the complexity and immunosuppressive nature of the lung cancer tumor microenvironment (TME). Tumor cells can evade immune surveillance and dampen overall immune responses through direct mechanisms such as secreting immunosuppressive cytokines, modulating T cell-mediated cytotoxicity, and downregulating major histocompatibility complex (MHC) expression (6), as well as indirect strategies by reprogramming the phenotypic and functional profiles of various stromal and immune cells within the TME, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and fibroblasts, to further shape an immunosuppressive niche (7,8).

Granulocyte-macrophage colony-stimulating factor (GM-CSF), a pleiotropic cytokine, was initially used for bone marrow protection in cancer patients after chemotherapy or radiotherapy due to its role in regulating neutrophil and monocyte proliferation and differentiation (9). With advances in tumor immunology, its immunomodulatory functions have gained increasing attention. GM-CSF can reshape the TME by promoting dendritic cells (DCs) maturation (10) and regulating macrophage polarization (11), both of which express GM-CSF receptor. However, its impact on T cell immunity is indirect and context-dependent. Through enhanced DC-mediated antigen presentation, GM-CSF-secreting tumor vaccines have been associated with increased T cell infiltration and antitumor responses in preclinical models and early-phase trials (12). Conversely, a randomized controlled trial in melanoma demonstrated that systemic, high-dose GM-CSF adjuvant therapy diminished antigen-specific T-cell immunity and was associated with worse clinical outcomes (13), likely through the expansion of immunosuppressive MDSCs. Since T cells themselves do not express GM-CSF receptor, these opposing effects underscore the critical role of GM-CSF’s actions on myeloid cells in dictating downstream T cell responses. Interestingly, GM-CSF exhibits dual immunomodulatory roles in various tumors including melanoma, breast cancer, and pancreatic cancer, acting either as an immunostimulant or an immunosuppressant (14-18). Similarly, the role of GM-CSF in lung cancer is significantly dualistic. On the one hand, GM-CSF can promote lung cancer cell proliferation and invasion by activating the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways and enhancing the activity of extracellular matrix-degrading proteases. On the other hand, it can exert anti-tumor effects by inducing DC differentiation, M1 macrophage polarization, neutrophil survival, natural killer (NK) cell terminal maturation, cell cycle arrest at the G0/G1 phase, and interleukin-12 (IL-12) secretion (19-24). The dual role of GM-CSF in cancer, particularly in lung cancer, has been extensively reviewed (25-27) highlighting the complexity of its context-dependent effects on tumor immunity and progression.

Regarding clinical translation, the immunotherapeutic potential of GM-CSF has been explored in several clinical trials. For instance, in the maintenance therapy for metastatic pancreatic ductal adenocarcinoma (PDA), a GM-CSF-secreting allogeneic pancreatic tumor vaccine (GVAX) combined with ipilimumab did not significantly improve overall survival (9.38 vs. 14.7 months) but promoted T cell differentiation towards an effector memory phenotype and increased the proportion of intratumoral M1 macrophages (28). Similarly, in a phase II trial for advanced ovarian cancer, the FRα vaccine TPIV200 combined with the programmed death-ligand 1 (PD-L1) inhibitor durvalumab showed a limited objective response rate (ORR) of 3.7%, yet all patients demonstrated significant FRα-specific T cell responses, with a median overall survival of 21 months (29). These clinical data suggest that the efficacy of GM-CSF may depend on its synergy with other immunomodulators and the specific characteristics of the TME. Therefore, a deeper understanding of the dual regulatory mechanisms of GM-CSF in lung cancer will aid in developing more precise immune combination strategies to overcome current therapeutic limitations. This review systematically summarizes the dual regulatory roles of GM-CSF in the lung cancer TME, elucidates its mechanisms of reshaping the functions of various immune cells, and focuses on its therapeutic potential in lung cancer, aiming to provide theoretical support for breaking through lung cancer treatment bottlenecks and optimizing precise combination strategies.

Biological characteristics of GM-CSF and its expression features in lung cancer

While GM-CSF is traditionally recognized for its role in myelopoiesis, it is important to note that it is not an essential regulator of steady-state hematopoiesis. Studies in GM-CSF-deficient mice revealed no major defects in baseline myeloid cell production (30). Instead, GM-CSF functions primarily as a key mediator of inflammation and ‘emergency’ hematopoiesis, where it is rapidly induced to mobilize and expand myeloid cell pools in response to local challenges (31). Notably, GM-CSF plays a non-redundant and indispensable role in the development and homeostasis of alveolar macrophages, the resident immune cells unique to the lung microenvironment (30,32). This lung-specific requirement underscores the particular relevance of GM-CSF biology in the context of lung cancer, where alveolar macrophages and recruited myeloid cells profoundly influence tumor progression and therapeutic responses. The well-defined molecular structure, cellular sources, and downstream signaling networks of GM-CSF establish a key biological foundation for its involvement in lung cancer pathogenesis (25). In lung cancer, the expression of GM-CSF and granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) exhibits significant heterogeneity across different types, and this expression variation is directly linked to core biological behaviors such as tumor proliferation and invasion. Clarifying the biological properties of GM-CSF, its expression patterns in lung cancer, and their associations with clinicopathological features and treatment responses is a core prerequisite for deciphering its role in lung cancer pathology and its clinical translational potential.

Structure, sources, and signaling pathways of GM-CSF

GM-CSF was initially purified as a small glycoprotein from the conditioned medium of lipopolysaccharide-treated mouse lung tissue, capable of promoting the proliferation of bone marrow-derived granulocytes and macrophages (33). In humans, the GM-CSF gene is located on the long arm of chromosome 5 at region q23–q31, spanning approximately 2.5 kb and containing 4 exons and 3 introns (34). Its encoded product is a single-chain glycoprotein consisting of 127 amino acids, with a molecular structure containing 4 α-helices and 2 β-sheets (34). GM-CSF is produced by a wide range of cells, including immune cells such as lymphocytes, macrophages, monocytes, mast cells, and granulocytes, as well as stromal cells like fibroblasts, endothelial cells, mesothelial cells, and osteoblasts. Furthermore, GM-CSF secretion can be detected in various solid tumors including lung cancer, breast cancer, and cholangiocarcinoma (11,35-39).

GM-CSFR composed of a specific α chain and a β chain (40). The α chain is unique to GM-CSFR, while the β chain is responsible for downstream signal transduction and is shared with the interleukin-3 (IL-3) and interleukin-5 (IL-5) receptors (41). GM-CSFR is expressed on various cells including tumor cells, monocytes, macrophages, and granulocytes (42). Notably, although T cells are a major source of GM-CSF secretion, they themselves do not express GM-CSFR (43). All biological activities of GM-CSF are mediated through its binding to and activation of the GM-CSFR. Upon ligand binding and receptor activation, the α and β chains of the GM-CSFR form a heterodimer, initiating multiple downstream signaling pathways such as janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) (44), PI3K/AKT (23), and MEK/ERK (23), thereby regulating cell proliferation, invasion, and survival. GM-CSF can also promote the release of inflammatory factors by activating the nuclear factor kappa B (NF-κB) pathway. This can, on the one hand, enhance the antigen-presenting function of DCs and activate T cell anti-tumor immunity (45); on the other hand, it may induce the differentiation of MDSCs, and influence the polarization of TAMs, with evidence supporting both pro-inflammatory (M1-type) and, in some contexts, anti-inflammatory (M2-type) phenotypes (27,46,47). This contributes to the formation of an immunosuppressive microenvironment (Figure 1).

Figure 1 Schematic summary of the structure, cellular sources, biological functions, and key signaling pathways of GM-CSF. ERK, extracellular signal-regulated kinase; GM-CSF, granulocyte-macrophage colony-stimulating factor; GM-CSFR, granulocyte-macrophage colony-stimulating factor receptor; IKK, inhibitor of nuclear factor kappa B kinase; JAK, janus kinase; MEK, mitogen-activated protein kinase; NF-κB, nuclear factor kappa B; PI3K, phosphatidylinositol 3-kinase; STAT5, signal transducer and activator of transcription 5.

Expression patterns of GM-CSF in lung cancer

GM-CSF is commonly dysregulated in different types of lung cancer tissues. In NSCLC, expression of both GM-CSF and GM-CSFR is frequently observed (48,49). Approximately 53% of primary NSCLC tissues show GM-CSF gene expression, and about 47% show GM-CSFR gene expression, with the expression rates of both being higher in lung adenocarcinoma than in lung squamous cell carcinoma (49). This trend is validated at the cellular level, with frequent GM-CSFR expression also found in NSCLC cell lines (50).

Compared to NSCLC, SCLC not only constitutively secretes GM-CSF but often co-expresses GM-CSFR (51). Gene microarray data analysis further indicates that GM-CSF gene expression levels in SCLC tissues are generally higher than in NSCLC (52). Notably, GM-CSF expression also shows significant heterogeneity among different molecular subtypes of SCLC: adherent-type SCLC, which is characterized by high expression of yes-associated protein 1 (YAP1) shows significantly higher GM-CSF expression than suspension-type SCLC, which displays high expression of achaete-scute homolog 1 (ASCL1) (53). Differences in GM-CSF expression directly influence treatment response and biological functions. Studies show that SCLC with low GM-CSF expression is more sensitive to targeted drugs such as anlotinib, chiauranib and everolimus compared to SCLC with high GM-CSF expression, and exhibits higher expression levels of drug-related targets vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and colony-stimulating factor 1 receptor (CSF1R). Silencing GM-CSF significantly enhances drug sensitivity to anlotinib, chiauranib, and everolimus, suppresses the expression of the SCLC subtype-related transcription factor YAP1, reduces the expression of the non-neuroendocrine (non-NE) marker cluster of differentiation 44 (CD44), and promotes the expression of the SCLC subtype-related transcription factor ASCL1 and the neuroendocrine (NE) marker synaptophysin (SYP) (53) (Figure 2).

Figure 2 Characterization of GM-CSF expression patterns in lung cancer and analysis of their correlation with clinical and pathological parameters. ASCL1, achaete-scute homolog 1; CD44, cluster of differentiation 44; GM-CSF, granulocyte-macrophage colony-stimulating factor; GM-CSFR, granulocyte-macrophage colony-stimulating factor receptor; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; SYP, synaptophysin; TNM, tumor node metastasis; YAP1, yes-associated protein 1.

Correlation between GM-CSF expression and clinical features of lung cancer

GM-CSF expression is closely associated with poor prognosis and specific pathological features in lung cancer patients. An analysis of 90 primary NSCLC specimens demonstrated that patients with squamous cell carcinoma co-expressing GM-CSF and its receptor had significantly poorer prognosis than those expressing neither (49). Studies also indicate that elevated serum GM-CSF levels serve as a marker for adverse clinical outcomes, a phenomenon particularly evident in NSCLC patients (54).

GM-CSF expression influences lung cancer progression. NSCLC patients with high GM-CSF expression are more prone to lymph node metastasis and vascular invasion, often accompanied by the activation of matrix metalloproteinases (MMPs) and increased activity of urokinase-type plasminogen activator (uPA), collectively leading to basement membrane destruction and promoting tumor invasion and metastasis (21,55). Serological studies also found that serum GM-CSF levels in NSCLC patients are significantly higher than in healthy individuals and positively correlate with tumor node metastasis (TNM) stage (56). Mechanistic studies reveal that high GM-CSF expression significantly positively correlates with the epithelial-mesenchymal transition (EMT) score in NSCLC (57). Moreover, various cell types within the lung cancer microenvironment, such as tumor-associated endothelial cells, can secrete GM-CSF, which promotes tumor angiogenesis and metastasis by upregulating the expression of cell adhesion molecules (58). Activation of downstream signaling pathways like MEK/ERK and PI3K/AKT by GM-CSF has also been confirmed to directly correlate with enhanced tumor cell proliferation and invasion capabilities (23). However, in SCLC, GM-CSF can slow tumor progression by inducing terminal differentiation of cancer stem cells and causing cell cycle arrest at the G0/G1 phase (22,24) (Figure 2).

Regulatory role of GM-CSF in the lung cancer TME

The TME is the core site regulating lung cancer initiation, progression, therapeutic resistance, and recurrence/metastasis. The composition and functional remodeling of immune cell subsets within it directly determine the strength and persistence of anti-tumor immune responses. As a key regulator bridging innate and adaptive immunity, GM-CSF exhibits complex dual regulatory characteristics within the lung cancer TME. Its core mechanism involves targeting key myeloid immune cells such as TAMs, MDSCs, tumor-associated neutrophils (TANs), and DCs. By regulating their differentiation, maturation, phenotypic polarization, and functional activity, GM-CSF deeply participates in the dynamic balance between the formation of the lung cancer immunosuppressive network and the activation of anti-tumor immunity (Figure 3).

Figure 3 Schematic illustration of the dual (pro-tumor and anti-tumor) role of GM-CSF in the lung cancer TME. APC, antigen-presenting cell; ARG1, secrete arginase 1; Bcl-xL, B-cell lymphoma-extra-large; CCL2, C-C motif chemokine ligand 2; CCR2, C-C motif chemokine receptor 2; CD86, cluster of differentiation 86; CD8, cluster of differentiation 8; CTL, cytotoxic T lymphocyte; DCs, dendritic cells; GM-CSF, granulocyte-macrophage colony-stimulating factor; HLA, human leukocyte antigen; IL-12, interleukin-12; IL-4, interleukin 4; IL-4Rα, interleukin-4 receptor α; JAK, janus kinase; MDSCs, myeloid-derived suppressor cells; STAT, signal transducer and activator of transcription; TAM, tumor-associated macrophages; TANs, tumor-associated neutrophils; Th1, T helper 1; TME, tumor microenvironment.

Regulation of TAMs by GM-CSF

TAMs are key pro-tumor immune cells in the lung cancer TME. Recruited into lung cancer tissues, TAMs can suppress anti-tumor immune responses and promote lung cancer proliferation, angiogenesis, metastasis, and therapy resistance by secreting pro-tumor factors and interfering with T cell function (59,60).

Historically, TAMs have been classified into pro-inflammatory (M1-type) and pro-tumor (M2-type) subsets based on in vitro studies (61). However, this binary framework is now widely recognized as an oversimplification that inadequately captures the complexity of TAM phenotypes in vivo (62). Recent advances in single-cell transcriptomics have revolutionized our understanding of TAM heterogeneity, and consensus reviews have proposed a refined nomenclature of TAM subsets conserved across multiple cancer types (63). Among these, at least two distinct types of inflammatory TAMs have been identified: interferon-primed TAMs (IFN-TAMs) and inflammatory cytokine-enriched TAMs (Inflam-TAMs), characterized by expression of interleukin 1 beta (IL-1β), C-X-C motif chemokine ligand 8 (CXCL8) and other inflammatory mediators (63). Notably, IFN-TAMs, despite their M1-type transcriptomic profile, have been shown to exert immunosuppressive functions (63).

The functional significance of Inflam-TAMs is further highlighted by studies linking them to GM-CSF. In melanoma, GM-CSF-primed macrophages acquire an Inflam-TAM-like phenotype associated with poor prognosis, with C-C motif chemokine ligand 20 (CCL20) emerging as a key secreted factor in this pro-tumoral axis (64). Of direct relevance to lung cancer, a single-cell RNA-seq atlas of NSCLC identified a CCL20⁺ TAM cluster correlated with patient prognosis, and functional experiments demonstrated that CCL20 knockdown reduced M2 polarization and inhibited tumor cell proliferation (65). These findings suggest that a GM-CSF-CCL20 axis may drive a pro-tumoral TAM subset in lung cancer analogous to the Inflam-TAMs described in other tumor types.

Against this backdrop of TAM heterogeneity, it is not surprising that the relationship between TAMs and patient prognosis in lung cancer remains controversial, as previous studies often relied on limited markers that do not capture this complexity. Multiple studies indicate that an increased number of cluster of differentiation 163-positive (CD163⁺) TAMs or cluster of differentiation 204-positive (CD204⁺) TAMs in tumor nests or stroma is closely associated with higher stage, presence of lymphovascular invasion, and poor prognosis in lung adenocarcinoma patients (66-69), and may be involved in EGFR-TKI resistance (70). However, some studies suggest no correlation between TAMs and prognosis in lung adenocarcinoma patients (71,72). In squamous cell carcinoma, the number of CD204⁺ TAMs in the tumor stroma (but not in tumor nests) correlates significantly with poor prognosis and microvessel density (73). In SCLC patients, one study showed that the number of infiltrating CD204⁺ TAMs had no impact on prognosis (74). Yet another study indicates that intercellular interactions between SCLC cells and TAMs can promote disease progression and chemotherapy resistance by activating the signal transducer and activator of transcription 3 (STAT3) pathway (75). A major reason for this controversy is the inherent tumor heterogeneity within different lung cancer types (e.g., lung adenocarcinoma itself has various histological subtypes or molecular subtypes) (76,77). Additionally, the use of different macrophage markers [cluster of differentiation 68 (CD68), CD204, cluster of differentiation 163 (CD163)] across studies (78,79), and failure to consider differences in macrophage distribution, morphology, and gene expression due to localization when evaluating TAMs are also primary reasons for inconsistent research results (80).

GM-CSF is primarily a factor inducing M1 macrophage polarization (81). It can induce an inflammatory phenotype in human monocytes by upregulating human leukocyte antigen (HLA)-DR and cluster of differentiation 86 (CD86) expression and increasing tumor necrosis factor alpha (TNF-α) and IL-1β production, thereby enhancing anti-tumor immune responses (82). GM-CSFR signaling can also induce TAM polarization towards an anti-tumor MHC-II high-expressing M1 phenotype (83). However, studies also show that GM-CSF can induce T cells to produce C-C motif chemokine ligand 2 (CCL2) in the TME and promote C-C motif chemokine receptor 2 (CCR2) expression on macrophages, thereby polarizing macrophages towards a pro-metastatic M2 phenotype (84,85). CCL2, acting through its receptor CCR2, can polarize macrophages towards a pro-metastatic M2 phenotype (85). While this mechanism has been established in experimental models and in vitro systems, its occurrence in human tumors—particularly in lung cancer—has been supported by subsequent studies showing that the CCL2/CCR2 axis promotes macrophage infiltration and M2 polarization in NSCLC, contributing to tumor progression and metastasis (86,87). Beyond its effects on macrophages and MDSCs, GM-CSF also exerts direct anti-tumor immune functions. In NSCLC, GM-CSF can enhance T lymphocyte immune responses by inducing M1 macrophage polarization. Simultaneously, GM-CSF promotes neutrophil survival and NK cell terminal maturation, thereby enhancing NK cell-mediated cytotoxicity against lung cancer (20).

Regulation of MDSCs by GM-CSF

MDSCs are a heterogeneous population derived from immature myeloid cells (IMCs). As precursors to macrophages, DCs, and granulocytes, they possess significant immunosuppressive functions (88). Based on morphological features resembling both granulocytes and monocytes, MDSCs are broadly classified into granulocytic (G) or polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs) (89,90). In recent years, another subtype of MDSCs, early-stage MDSCs (e-MDSCs), has been identified in human peripheral blood. These cells lack features of monocytes and granulocytes and are in an immature state (90). MDSCs can mediate tumor escape and growth by promoting tumor angiogenesis, lymphangiogenesis, and pre-metastatic niche formation in preclinical mouse models (91-93). Furthermore, MDSCs possess potent immunosuppressive activity, capable of inhibiting the functions of cluster of differentiation 4-positive (CD4⁺) T cells, cluster of differentiation 8-positive (CD8⁺) T cells, and NK cells (94). However, it is important to note a key species difference: while MDSCs are abundantly present and well-characterized within solid tumors in mouse models, in human cancers—including lung cancer—MDSCs are primarily detected in the peripheral blood rather than within the tumor tissue itself (95). Within the human TME, immunosuppression is predominantly mediated by TAMs, which are more abundant and constitute the major myeloid population (96). MDSCs may contribute to intratumoral immunosuppression indirectly by serving as precursors that differentiate into TAMs within the TME (97).

In lung cancer, MDSC levels are generally elevated. These MDSCs can promote tumor progression by inhibiting CD8⁺ T cell function and are associated with poor prognosis (98). In SCLC patients, the number and frequency of cluster of differentiation 14-positive (CD14⁺) HLA-DR-MDSCs and cluster of differentiation 33-positive (CD33⁺) HLA-DR-MDSCs in peripheral blood are significantly increased, and CD14⁺ HLA-DR-/low MDSCs serve as an independent biomarker for poor prognosis in SCLC patients (99,100). Similar observations are made in NSCLC patients’ peripheral blood and PBMCs. Patients with high MDSC levels have significantly shorter overall survival, and monocytic MDSCs suppress T cell function via the nicotinamide adenine dinucleotide phosphate (NADPH)/ROS pathway (101,102). Moreover, MDSCs in lung cancer are associated with resistance to chemotherapy, targeted therapy, and immunotherapy (102-106).

GM-CSF is a key cytokine inducing the expansion and activation of MDSCs in lung cancer, mediating immunosuppression through MDSCs (37,107). GM-CSF can enhance the expression of interleukin 4 receptor alpha (IL-4Rα) on MDSCs (108). Upon interleukin 4 (IL-4) stimulation, MDSCs secrete arginase 1 (ARG1) (109), depleting arginine in the TME and thereby impairing T cell activation and function (110). In a lung adenocarcinoma mouse model, reducing ARG1 expression in MDSCs alleviated L-arginine depletion in the TME and reversed T cell dysfunction (111). High-dose GM-CSF-induced cluster of differentiation 11b-positive (CD11b⁺), granulocyte receptor 1-positive (Gr1⁺) MDSCs can also produce nitric oxide (NO) via the inducible nitric oxide synthase (iNOS) pathway, inhibiting T cell function in models of lymphoma and melanoma (112). Interestingly, the impact of NO on anti-tumor immunity appears to be highly context-dependent. In contrast to MDSC-derived NO, which suppresses T cell responses, therapeutic administration of ultra-high concentration gaseous nitric oxide (UHCgNO) in a Lewis lung carcinoma mouse model increased the infiltration of DCs, T cells, and B cells into tumors, promoting anti-tumor responses (113). This dichotomy underscores that the source, concentration, and delivery method of NO critically determine its net effect on the TME. Furthermore, consistent with the immunosuppressive role of endogenous iNOS, iNOS has been identified as a negative regulator of radiotherapy-induced anti-tumor immunity; combining radiotherapy with iNOS blockade synergistically enhanced anti-tumor immune responses in a Lewis lung carcinoma model (114).

Effect of GM-CSF on TANs

TANs are important inflammatory cells in the TME. Unlike most other tissues, the lung harbors a significant reservoir of marginated neutrophils within its vascular bed under homeostatic conditions, serving as first-line defenders against inhaled pathogens and particulates (115). In lung cancer, TANs are recruited and shaped by the TME, and they constitute a prominent component of the immune infiltrate in NSCLC (116,117). However, a critical caveat must be noted when interpreting findings from preclinical models: while neutrophils and PMN-MDSCs are abundantly present in murine tumors, their prominence in human tumors varies considerably across cancer types and is particularly well-documented in lung cancer, cautioning against broad generalizations from mouse to human (118). Mechanistically, tumor cell-derived GM-CSF promotes TAN survival via the JAK/STAT signaling pathway and upregulation of B-cell lymphoma-extra-large (Bcl-xL), contributing to their accumulation in the lung TME (119).

Once recruited and sustained within the TME, TANs exhibit functional plasticity and can differentiate into distinct phenotypes (120). As key components of innate immunity, TANs can differentiate into anti-tumor N1 type and pro-tumor N2 type (121). N1 TANs can directly kill tumor cells or inhibit their proliferation by releasing cytotoxic mediators such as reactive oxygen species (ROS) and myeloperoxidase (MPO) (122). N2 TANs highly express ARG1, certain chemokine ligands like CCL2 and interleukin 8 (IL-8)/CXCL8, and produce neutrophil gelatinase-associated lipocalin (NGAL), participating in immunosuppression, angiogenesis, and tumor invasion/metastasis (123-125).

Tumor-derived GM-CSF can induce TAN activation and proliferation (25). Hepatocellular carcinoma-derived GM-CSF stimulates cancer cell migration and invasion by inducing hepatocyte growth factor (HGF) production in TANs and activating the HGF/cellular-mesenchymal epithelial transition factor (c-Met) axis (126). In a genetically engineered mouse model of lung adenocarcinoma, tumor cell-derived GM-CSF promoted the expression of Bcl-xL via the JAK/STAT signaling pathway, enhancing the survival of pro-tumor TANs. Using the Bcl-xL inhibitor A-1331852 selectively reduced the abundance of pro-tumor TANs and increased anti-tumor TANs (119). However, in early-stage human lung cancer, a subset of TANs exhibits antigen-presenting cell (APC)-like characteristics (127). Interferon gamma (IFN-γ) and GM-CSF promote these APC-like features in some immature neutrophils by downregulating the transcription factor Ikaros (128). APC-like TAN1 expresses CD86 and HLA-DR and can enhance the anti-tumor effects of T cells (129,130). Targeting the programmed death protein 1 (PD-1)/PD-L1 axis is not only an effective immunotherapy for various cancers but also a strategy to target TANs (131,132). Studies show that GM-CSF secreted by the TME can induce PD-L1 expression on TANs via the JAK/STAT3 signaling pathway (133). PD-L1⁺ TANs typically negatively regulate T cells, suppressing their immune functions and accelerating tumor progression (134). Conversely, TAN-derived GM-CSF can exert anti-tumor effects. In lung cancer, TANs can inhibit tumors by producing GM-CSF to activate T cells (120).

Effect of GM-CSF on DCs

DCs, as APCs in the TME, require functional activation to initiate anti-tumor immunity. GM-CSF promotes DCs differentiation, maturation, and expansion, triggering the antigen recognition process and presentation of tumor antigens to T cells, thereby further enhancing anti-tumor immunity (43). As comprehensively reviewed by Zhan et al., GM-CSF acts as a ‘rheostat’ that not only drives the development of DCs from progenitors but also finely tunes their functional properties in a dose-dependent manner, with important implications for cancer immunotherapy (135). Regarding the presence of DCs within human tumors, recent studies have confirmed that conventional DC subsets (cDC1 and cDC2) are detectable in lung cancer tissues, although their abundance is relatively low compared to other myeloid populations (136,137). Importantly, the spatial distribution of DCs within the TME—including their localization to stromal regions and tertiary lymphoid structures—correlates with T cell infiltration and patient outcomes (136). Furthermore, baseline infiltration of specific DC subsets, such as C-C motif chemokine ligand 19-positive (CCL19⁺) DCs, has been shown to predict immunotherapy responses in lung adenocarcinoma patients, underscoring their clinical relevance despite their numerical scarcity (138). These findings highlight that the functional impact of DCs in the TME is determined not only by their abundance but also by their activation state, spatial organization, and interactions with other immune cells. Given the central role of GM-CSF in orchestrating DC biology, these observations raise the possibility that GM-CSF-mediated regulation of DC differentiation and function may underlie their clinical impact. Mechanistically, GM-CSF regulates DCs differentiation via the JAK2-STAT5 and MEK/ERK signaling pathways, while the downstream PI3K-protein kinase B (PKB) pathway primarily promotes the expansion and survival of DCs precursors without participating in their differentiation (45). In a Lewis lung carcinoma mouse model, GM-CSF activated DCs, promoted their functional maturation and IL-12 secretion, thereby activating Th1-type adaptive immunity. Combining Fas ligand (FasL) with GM-CSF-activated DCs showed synergistic anti-tumor effects (19). Furthermore, GM-CSF combined with IL-4 can promote the differentiation of monocytes from lung cancer patient peripheral blood into classical DCs. GM-CSF, IL-4, and TNF-α combined can effectively induce a sufficient number of DCs from mature macrophages derived from malignant pleural effusions (139), suggesting the potential of GM-CSF in DCs-based immunotherapy for lung cancer.

Therapeutic potential of GM-CSF in lung cancer

As a pleiotropic cytokine with both hematopoietic support and immunomodulatory functions, the therapeutic landscape of GM-CSF in lung cancer has evolved from its initial use for bone marrow support during radiotherapy/chemotherapy to multi-modal combination immunotherapy. Relevant clinical studies provide key evidence for its application value and optimization strategies.

Bone marrow function protection during radiotherapy/chemotherapy

The initial therapeutic application of GM-CSF in lung cancer focused on ameliorating radiotherapy/chemotherapy-induced myelosuppression, an effect validated in both NSCLC and SCLC. Clinical studies confirmed that it specifically promotes the proliferation of hematopoietic cells like neutrophils and monocytes, significantly aiding bone marrow recovery after cytotoxic therapy (140). Moreover, by potentially reducing the acute toxicity of chemotherapy, GM-CSF could ultimately improve complete response rates and increase the number of patients with long-term disease-free survival, an effect particularly notable in SCLC (140). A prospective study in advanced NSCLC showed that prophylactic use of GM-CSF in dose-intensified therapy improved patient tolerance to chemotherapy by reducing the severity of granulocytopenia and accelerating neutrophil recovery (141). In SCLC, a randomized multicenter dose-finding study further established that recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) administered at 5–10 µg/kg alleviated chemotherapy-associated neutropenia. The antibiotic use rate in the 10 µg/kg rhGM-CSF group (11%) was significantly lower than in the control group (29%), confirming the safety and efficacy within this dose range (142).

Safety and preliminary efficacy of local administration strategies

Nebulized inhalation, as a lung-specific targeted delivery method, demonstrated good tolerability in a Phase I study involving patients with lung metastases or primary lung cancer using a regimen of 250 µg/dose, twice daily, for one week on/one week off. No significant pulmonary function impairment or severe systemic toxicity was observed. Among 45 patients, 24 achieved stable disease (SD) or partial response (PR). Notably, one patient with melanoma lung metastases showed a tenfold increase in tumor-specific T lymphocytes, suggesting local immune activation (143).

Combination with radiotherapy/chemotherapy and targeted therapy

In NSCLC, combining GM-CSF with radiotherapy/chemotherapy not only significantly reduced the incidence of myelosuppression but also identified anticipated administration of GM-CSF as an independent prognostic factor for locally advanced and metastatic NSCLC, with benefits primarily attributed to its protective effects on myeloid progenitors (141). A clinical study in EGFR-mutant advanced NSCLC showed that a triple regimen of GM-CSF combined with icotinib and local radiotherapy achieved an ORR of 95.24%, significantly higher than the icotinib monotherapy group (71.43%). This combination also upregulated the proportions of peripheral blood CD3⁺ and CD4⁺ T cells and the CD4⁺/CD8⁺ ratio, and significantly prolonged the annual progression-free survival (PFS) (144). Studies on such combination regimens in SCLC are relatively limited. A Phase II trial of the prodrug PR104 in SCLC explicitly excluded the initial combination with GM-CSF, suggesting that synergistic strategies combining radiotherapy/chemotherapy/targeted therapy with GM-CSF in SCLC require further validation (NCT00544674).

Combination with ICIs

With the widespread application of ICIs in lung cancer treatment, exploration into the potential of combining GM-CSF with ICIs has progressed. A single-arm open-label Phase II clinical study demonstrated the notable salvage therapeutic value of a PD-1 inhibitor combined with radiotherapy and GM-CSF in chemotherapy-resistant metastatic lung cancer and other solid tumors. The disease control rate (DCR) was 46.3%, median overall survival (OS) was 10.5 months, and the incidence of Grade 3–4 treatment-related adverse events (TRAEs) was only 12% (145). The multicenter Phase II SWORD trial (NCT04106180) evaluated the efficacy and safety of sintilimab (a PD-1 inhibitor) combined with stereotactic body radiotherapy (SBRT) and GM-CSF as second-line therapy for metastatic NSCLC (146). Results showed an ORR of 36.7%, median PFS of 5.9 months, and median OS of 18.4 months in the combination group, indicating significant clinical benefit and good safety. The incidence of Grade 3 TRAEs was only 11.8%, with no Grade 4-5 TRAEs, demonstrating good tolerability and promising efficacy for this triple therapy (146). However, clinical data on combining GM-CSF with newer agents like CAR-T cells, TIGIT inhibitors, or bispecific antibodies remain scarce, currently in early exploratory stages. There is a lack of clear Phase I/II trial results, and no mature data support its use in either NSCLC or SCLC within these novel combinations.

Discussion

GM-CSF exhibits a complex and paradoxical dual role within the lung cancer TME. On the one hand, it can act as an immunological “activator” by promoting DCs differentiation and maturation, inducing M1-type TAM polarization, enhancing the anti-tumor antigen-presenting function of TANs, and supporting T cell infiltration. On the other hand, it is a potent immunological “disruptor,” capable of expanding and activating MDSCs, inducing pro-tumor M2-type TAMs and N2-type TANs (27), and directly driving tumor cell proliferation, invasion, and EMT by activating signaling pathways such as MEK/ERK and PI3K/AKT within tumor cells (23). This duality is not coincidental but rather an inevitable consequence of its pleiotropy, which is regulated by specific cellular contexts, signaling networks, and pathological stages within the highly heterogeneous lung cancer TME.

Based on these intricate mechanisms, the exploration of GM-CSF’s application in lung cancer clinical therapy has evolved from initial use for bone marrow support during chemo/radiotherapy to combination strategies with ICIs, radiotherapy, and others. However, as trials like SWORD indicate, despite the promising prospects of combination regimens, efficacy remains heterogeneous (146). The fundamental reason lies in the current therapeutic paradigms’ inability to achieve precise intervention within the GM-CSF network.

To overcome the “double-edged sword” dilemma of GM-CSF and effectively translate it into clinical benefit, breakthroughs are urgently needed in the following dimensions:

• Firstly, at the level of basic research, a deep transition from “descriptive correlation” to “causal dissection” and “dynamic observation” is imperative. Current studies predominantly focus on describing the correlation between GM-CSF and the abundance of specific cell populations or patient prognosis. Future research must utilize lung cancer genetically engineered mouse models, organoid co-culture systems, and integrate single-cell multi-omics [e.g., single-cell RNA sequencing (scRNA-seq), single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq)] and spatial transcriptomics technologies to elucidate, at single-cell resolution: (I) how GM-CSF precisely determines the fate decision of the same precursor cell (e.g., a monocyte) to differentiate into anti-tumor DCs vs. pro-tumor MDSCs; (II) within the specific TME of different lung cancer subtypes, which co-existing cytokines or metabolites crosstalk with GM-CSF signaling to ultimately determine the phenotypic polarization direction of TAMs and TANs; (III) whether there exists a dominant sequence or feedback loop between the direct pro-growth effect of GM-CSF on tumor cells and its indirect immunomodulatory effects. The precise dissection of these mechanisms is the prerequisite for identifying key regulatory nodes.
• Secondly, at the translational and clinical level, the core imperative is to evolve therapeutic strategies from “generalized combination” towards “precise stratification” and “temporal optimization.” This involves discovering and validating biomarkers predictive of GM-CSF functional orientation. For instance, patients with high GM-CSFR expression on tumor cells accompanied by evidence of GM-CSF-driven PI3K/AKT pathway activation—which has been demonstrated in neutrophils and myeloid progenitors where GM-CSF induces AKT phosphorylation that can be blocked by PI3K inhibitors (147-150)—may benefit more from inhibitors targeting the GM-CSF/GM-CSFR axis. This therapeutic strategy should be distinguished from cases where PI3K/AKT activation results from somatic mutations (e.g., PIK3CA mutations), which drive pathway activation independently of GM-CSF signaling and may instead require alternative approaches such as PI3K inhibitors or aspirin combination therapy (151). Regarding combination strategies, more logically designed regimens should be considered. For patients exhibiting GM-CSF-mediated immunosuppressive TME features, sequential “disrupt-then-activate” therapy could be explored. This involves first using GM-CSF antagonists or MDSC-targeting agents to remove the inhibitory barrier, followed by introducing GM-CSF-based vaccines or cytokine therapy to activate immunity. Furthermore, the timing, sequence, and dosage of combining GM-CSF with different therapies (radiotherapy, chemotherapy, targeted drugs, ICIs) need systematic evaluation to identify the optimal window maximizing synergistic effects while minimizing pro-tumor risks.
• Finally, at the level of technological intervention, active development and evaluation of novel targeting tools and delivery systems are warranted. Beyond developing new small-molecule inhibitors or bispecific antibodies that selectively block the pro-tumor downstream pathways of GM-CSF while preserving its immune-stimulatory functions, exploring the use of oncolytic viruses or vaccines to express GM-CSF specifically within the tumor locale could achieve more controllable local immune activation, avoiding systemic side effects. However, it is important to note that clinical experience with talimogene laherparepvec (T-VEC), the most extensively studied GM-CSF-encoding oncolytic virus, has shown limited efficacy beyond melanoma, with promising results largely confined to this tumor type (152,153). These findings underscore that the success of such localized GM-CSF delivery strategies may be highly context-dependent and require careful optimization for specific tumor types, including lung cancer. Concurrently, delivery systems based on biomaterials designed for sustained release hold promise for maintaining the optimal therapeutic concentration of GM-CSF within the tumor region, thereby more precisely shaping a favorable immune microenvironment.

Conclusions

The duality of GM-CSF in lung cancer underscores the high degree of tumor heterogeneity and the complexity of immune regulation in this disease. Future research should move beyond simplistic attempts to categorize GM-CSF as a “good” or “bad” molecule. Instead, efforts should be dedicated to mapping its precise action atlas across different lung cancer contexts and, based on this, developing spatiotemporally precise and strategically intelligent intervention methods. This will ultimately enable GM-CSF to become an effective component of personalized therapy for lung cancer.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1470/prf

Funding: This work was supported by the Department of Science and Technology of Jilin Province (No. YDZJ202301ZYTS512) and the Health and Family Planning Commission of Jilin Province (No. 2023JC064).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1470/coif). The authors have no 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
2. Li Q, Yuan D, Ma C, et al. A new hope: the immunotherapy in small cell lung cancer. Neoplasma 2016;63:342-50. [Crossref] [PubMed]
3. Molina JR, Yang P, Cassivi SD, et al. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008;83:584-94. [Crossref] [PubMed]
4. Travis WD, Brambilla E, Nicholson AG, et al. The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification. J Thorac Oncol 2015;10:1243-60. [Crossref] [PubMed]
5. Mazieres J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol 2019;30:1321-8. [Crossref] [PubMed]
6. Massarelli E, Papadimitrakopoulou V, Welsh J, et al. Immunotherapy in lung cancer. Transl Lung Cancer Res 2014;3:53-63. [Crossref] [PubMed]
7. Galassi C, Chan TA, Vitale I, et al. The hallmarks of cancer immune evasion. Cancer Cell 2024;42:1825-63. [Crossref] [PubMed]
8. Tufail M, Jiang CH, Li N. Immune evasion in cancer: mechanisms and cutting-edge therapeutic approaches. Signal Transduct Target Ther 2025;10:227. [Crossref] [PubMed]
9. Vadhan-Raj S, Buescher S, LeMaistre A, et al. Stimulation of hematopoiesis in patients with bone marrow failure and in patients with malignancy by recombinant human granulocyte-macrophage colony-stimulating factor. Blood 1988;72:134-41.
10. Caux C, Dezutter-Dambuyant C, Schmitt D, et al. GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells. Nature 1992;360:258-61. [Crossref] [PubMed]
11. Becher B, Tugues S, Greter M GM-CSF. From Growth Factor to Central Mediator of Tissue Inflammation. Immunity 2016;45:963-73. [Crossref] [PubMed]
12. Dranoff G. GM-CSF-based cancer vaccines. Immunol Rev 2002;188:147-54. [Crossref] [PubMed]
13. Faries MB, Hsueh EC, Ye X, et al. Effect of granulocyte/macrophage colony-stimulating factor on vaccination with an allogeneic whole-cell melanoma vaccine. Clin Cancer Res 2009;15:7029-35. [Crossref] [PubMed]
14. Comunanza V, Gigliotti C, Lamba S, et al. Dual VEGFA/BRAF targeting boosts PD-1 blockade in melanoma through GM-CSF-mediated infiltration of M1 macrophages. Mol Oncol 2023;17:1474-91. [Crossref] [PubMed]
15. Hood JL. Melanoma exosome induction of endothelial cell GM-CSF in pre-metastatic lymph nodes may result in different M1 and M2 macrophage mediated angiogenic processes. Med Hypotheses 2016;94:118-22. [Crossref] [PubMed]
16. Guo Y, Hu Y, Huang D, et al. Dual roles of GM-CSF in breast cancer: Immunomodulation and therapeutic implications. Crit Rev Oncol Hematol 2025;214:104804. [Crossref] [PubMed]
17. Pylayeva-Gupta Y, Lee KE, Hajdu CH, et al. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 2012;21:836-47. [Crossref] [PubMed]
18. Le DT, Lutz E, Uram JN, et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother 2013;36:382-9. [Crossref] [PubMed]
19. Ho MY, Sun GH, Leu SJ, et al. Combination of Fasl and GM-CSF confers synergistic antitumor immunity in an in vivo model of the murine Lewis lung carcinoma. Int J Cancer 2008;123:123-33. [Crossref] [PubMed]
20. Lian GY, Wang QM, Mak TS, et al. Disrupting Smad3 potentiates immunostimulatory function of NK cells against lung carcinoma by promoting GM-CSF production. Cell Mol Life Sci 2024;81:262. [Crossref] [PubMed]
21. Pei XH, Nakanishi Y, Takayama K, et al. Granulocyte, granulocyte-macrophage, and macrophage colony-stimulating factors can stimulate the invasive capacity of human lung cancer cells. Br J Cancer 1999;79:40-6. [Crossref] [PubMed]
22. Ruff MR, Farrar WL, Pert CB. Interferon gamma and granulocyte/macrophage colony-stimulating factor inhibit growth and induce antigens characteristic of myeloid differentiation in small-cell lung cancer cell lines. Proc Natl Acad Sci U S A 1986;83:6613-7. [Crossref] [PubMed]
23. Uemura Y, Kobayashi M, Nakata H, et al. Effects of GM-CSF and M-CSF on tumor progression of lung cancer: roles of MEK1/ERK and AKT/PKB pathways. Int J Mol Med 2006;18:365-73.
24. Yamashita Y, Nara N, Aoki N. Antiproliferative and differentiative effect of granulocyte-macrophage colony-stimulating factor on a variant human small cell lung cancer cell line. Cancer Res 1989;49:5334-8.
25. Park Y, Chung C. Immune Evasion of G-CSF and GM-CSF in Lung Cancer. Tuberc Respir Dis (Seoul) 2024;87:22-30. [Crossref] [PubMed]
26. Hong IS. Stimulatory versus suppressive effects of GM-CSF on tumor progression in multiple cancer types. Exp Mol Med 2016;48:e242. [Crossref] [PubMed]
27. Kumar A, Taghi Khani A, Sanchez Ortiz A, et al. GM-CSF: A Double-Edged Sword in Cancer Immunotherapy. Front Immunol 2022;13:901277. [Crossref] [PubMed]
28. Wu AA, Bever KM, Ho WJ, et al. A Phase II Study of Allogeneic GM-CSF-Transfected Pancreatic Tumor Vaccine (GVAX) with Ipilimumab as Maintenance Treatment for Metastatic Pancreatic Cancer. Clin Cancer Res 2020;26:5129-39. [Crossref] [PubMed]
29. Zamarin D, Walderich S, Holland A, et al. Safety, immunogenicity, and clinical efficacy of durvalumab in combination with folate receptor alpha vaccine TPIV200 in patients with advanced ovarian cancer: a phase II trial. J Immunother Cancer 2020;8:e000829. [Crossref] [PubMed]
30. Stanley E, Lieschke GJ, Grail D, et al. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci U S A 1994;91:5592-6. [Crossref] [PubMed]
31. Louis C, Cook AD, Lacey D, et al. Specific Contributions of CSF-1 and GM-CSF to the Dynamics of the Mononuclear Phagocyte System. J Immunol 2015;195:134-44. [Crossref] [PubMed]
32. Guilliams M, De Kleer I, Henri S, et al. Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. J Exp Med 2013;210:1977-92. [Crossref] [PubMed]
33. Shiomi A, Usui T. Pivotal roles of GM-CSF in autoimmunity and inflammation. Mediators Inflamm 2015;2015:568543. [Crossref] [PubMed]
34. Barreda DR, Hanington PC, Belosevic M. Regulation of myeloid development and function by colony stimulating factors. Dev Comp Immunol 2004;28:509-54. [Crossref] [PubMed]
35. Gasson JC. Molecular physiology of granulocyte-macrophage colony-stimulating factor. Blood 1991;77:1131-45.
36. Lotfi N, Thome R, Rezaei N, et al. Roles of GM-CSF in the Pathogenesis of Autoimmune Diseases: An Update. Front Immunol 2019;10:1265. [Crossref] [PubMed]
37. Aliper AM, Frieden-Korovkina VP, Buzdin A, et al. A role for G-CSF and GM-CSF in nonmyeloid cancers. Cancer Med 2014;3:737-46. [Crossref] [PubMed]
38. Ruffolo LI, Jackson KM, Kuhlers PC, et al. GM-CSF drives myelopoiesis, recruitment and polarisation of tumour-associated macrophages in cholangiocarcinoma and systemic blockade facilitates antitumour immunity. Gut 2022;71:1386-98. [Crossref] [PubMed]
39. Su X, Xu Y, Fox GC, et al. Breast cancer-derived GM-CSF regulates arginase 1 in myeloid cells to promote an immunosuppressive microenvironment. J Clin Invest 2021;131:e145296. [Crossref] [PubMed]
40. Hansen G, Hercus TR, McClure BJ, et al. The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation. Cell 2008;134:496-507. [Crossref] [PubMed]
41. Kumar A, Rani L, Mhaske ST, et al. IL-3 Receptor Expression on Activated Human Th Cells Is Regulated by IL-4, and IL-3 Synergizes with IL-4 to Enhance Th2 Cell Differentiation. J Immunol 2020;204:819-31. [Crossref] [PubMed]
42. Hamilton JA. GM-CSF in inflammation. J Exp Med 2020;217:e20190945. [Crossref] [PubMed]
43. Shi Y, Liu CH, Roberts AI, et al. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don't know. Cell Res 2006;16:126-33. [Crossref] [PubMed]
44. Guthridge MA, Powell JA, Barry EF, et al. Growth factor pleiotropy is controlled by a receptor Tyr/Ser motif that acts as a binary switch. EMBO J 2006;25:479-89. [Crossref] [PubMed]
45. van de Laar L, Coffer PJ, Woltman AM. Regulation of dendritic cell development by GM-CSF: molecular control and implications for immune homeostasis and therapy. Blood 2012;119:3383-93. [Crossref] [PubMed]
46. Liu C, Qiang J, Deng Q, et al. ALDH1A1 Activity in Tumor-Initiating Cells Remodels Myeloid-Derived Suppressor Cells to Promote Breast Cancer Progression. Cancer Res 2021;81:5919-34. [Crossref] [PubMed]
47. Sami E, Paul BT, Koziol JA, et al. The Immunosuppressive Microenvironment in BRCA1-IRIS-Overexpressing TNBC Tumors Is Induced by Bidirectional Interaction with Tumor-Associated Macrophages. Cancer Res 2020;80:1102-17. [Crossref] [PubMed]
48. Asselin-Paturel C, Echchakir H, Carayol G, et al. Quantitative analysis of Th1, Th2 and TGF-beta1 cytokine expression in tumor, TIL and PBL of non-small cell lung cancer patients. Int J Cancer 1998;77:7-12. [Crossref] [PubMed]
49. Oshika Y, Nakamura M, Abe Y, et al. Growth stimulation of non-small cell lung cancer xenografts by granulocyte-macrophage colony-stimulating factor (GM-CSF). Eur J Cancer 1998;34:1958-61. [Crossref] [PubMed]
50. Miyagawa K, Chiba S, Shibuya K, et al. Frequent expression of receptors for granulocyte-macrophage colony-stimulating factor on human nonhematopoietic tumor cell lines. J Cell Physiol 1990;143:483-7. [Crossref] [PubMed]
51. Baldwin GC, Gasson JC, Kaufman SE, et al. Nonhematopoietic tumor cells express functional GM-CSF receptors. Blood 1989;73:1033-7.
52. Bhattacharjee A, Richards WG, Staunton J, et al. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci U S A 2001;98:13790-5. [Crossref] [PubMed]
53. Li H, Zhong R, He C, et al. Colony stimulating factor CSF2 mediates the phenotypic plasticity of small cell lung cancer by regulating the p STAT3/MYC pathway. Oncol Rep 2022;48:122. [Crossref] [PubMed]
54. Mroczko B, Szmitkowski M. Hematopoietic cytokines as tumor markers. Clin Chem Lab Med 2004;42:1347-54. [Crossref] [PubMed]
55. Levina V, Marrangoni AM, DeMarco R, et al. Drug-selected human lung cancer stem cells: cytokine network, tumorigenic and metastatic properties. PLoS One 2008;3:e3077. [Crossref] [PubMed]
56. Mroczko B, Szmitkowski M, Furman M, et al. Granulocyte macrophage-colony stimulating factor (GM-CSF) in diagnosis and monitoring of non-small cell lung cancer. Pol Arch Med Wewn 1998;99:195-202.
57. Rudisch A, Dewhurst MR, Horga LG, et al. High EMT Signature Score of Invasive Non-Small Cell Lung Cancer (NSCLC) Cells Correlates with NFkappaB Driven Colony-Stimulating Factor 2 (CSF2/GM-CSF) Secretion by Neighboring Stromal Fibroblasts. PLoS One 2015;10:e0124283. [Crossref] [PubMed]
58. Chen C, Duckworth CA, Zhao Q, et al. Increased circulation of galectin-3 in cancer induces secretion of metastasis-promoting cytokines from blood vascular endothelium. Clin Cancer Res 2013;19:1693-704. [Crossref] [PubMed]
59. Zhou Y, Qian M, Li J, et al. The role of tumor-associated macrophages in lung cancer: From mechanism to small molecule therapy. Biomed Pharmacother 2024;170:116014. [Crossref] [PubMed]
60. Zhu R, Huang J, Qian F. The role of tumor-associated macrophages in lung cancer. Front Immunol 2025;16:1556209. [Crossref] [PubMed]
61. Greene HL, Phillips BL, Franck L, et al. Persistently low blood retinol levels during and after parenteral feeding of very low birth weight infants: examination of losses into intravenous administration sets and a method of prevention by addition to a lipid emulsion. Pediatrics 1987;79:894-900.
62. Tsukamoto H, Komohara Y, Oshiumi H. The role of macrophages in anti-tumor immune responses: pathological significance and potential as therapeutic targets. Hum Cell 2021;34:1031-9. [Crossref] [PubMed]
63. Ma RY, Black A, Qian BZ. Macrophage diversity in cancer revisited in the era of single-cell omics. Trends Immunol 2022;43:546-63. [Crossref] [PubMed]
64. García-Martínez E, Nieto-Valle A, Barrio-Alonso C, et al. Adverse prognosis of GM-CSF expression in human cutaneous melanoma. Neoplasia 2025;70:101240. [Crossref] [PubMed]
65. Wen S, Zou R, Du X, et al. Identification of macrophage-related genes correlated with prognosis and immunotherapy efficacy in non-small cell lung cancer. Heliyon 2024;10:e27170. [Crossref] [PubMed]
66. Ohtaki Y, Ishii G, Nagai K, et al. Stromal macrophage expressing CD204 is associated with tumor aggressiveness in lung adenocarcinoma. J Thorac Oncol 2010;5:1507-15. [Crossref] [PubMed]
67. Kaseda K, Ishii G, Aokage K, et al. Identification of intravascular tumor microenvironment features predicting the recurrence of pathological stage I lung adenocarcinoma. Cancer Sci 2013;104:1262-9. [Crossref] [PubMed]
68. Ito M, Ishii G, Nagai K, et al. Prognostic impact of cancer-associated stromal cells in patients with stage I lung adenocarcinoma. Chest 2012;142:151-8. [Crossref] [PubMed]
69. Ohri CM, Shikotra A, Green RH, et al. The tissue microlocalisation and cellular expression of CD163, VEGF, HLA-DR, iNOS, and MRP 8/14 is correlated to clinical outcome in NSCLC. PLoS One 2011;6:e21874. [Crossref] [PubMed]
70. Chung FT, Lee KY, Wang CW, et al. Tumor-associated macrophages correlate with response to epidermal growth factor receptor-tyrosine kinase inhibitors in advanced non-small cell lung cancer. Int J Cancer 2012;131:E227-35. [Crossref] [PubMed]
71. Carus A, Ladekarl M, Hager H, et al. Tumor-associated neutrophils and macrophages in non-small cell lung cancer: no immediate impact on patient outcome. Lung Cancer 2013;81:130-7. [Crossref] [PubMed]
72. Ma J, Liu L, Che G, et al. The M1 form of tumor-associated macrophages in non-small cell lung cancer is positively associated with survival time. BMC Cancer 2010;10:112. [Crossref] [PubMed]
73. Hirayama S, Ishii G, Nagai K, et al. Prognostic impact of CD204-positive macrophages in lung squamous cell carcinoma: possible contribution of Cd204-positive macrophages to the tumor-promoting microenvironment. J Thorac Oncol 2012;7:1790-7. [Crossref] [PubMed]
74. Takahashi A, Ishii G, Kinoshita T, et al. Identification of prognostic immunophenotypic features in cancer stromal cells of high-grade neuroendocrine carcinomas of the lung. J Cancer Res Clin Oncol 2013;139:1869-78. [Crossref] [PubMed]
75. Iriki T, Ohnishi K, Fujiwara Y, et al. The cell-cell interaction between tumor-associated macrophages and small cell lung cancer cells is involved in tumor progression via STAT3 activation. Lung Cancer 2017;106:22-32. [Crossref] [PubMed]
76. Wu F, Fan J, He Y, et al. Single-cell profiling of tumor heterogeneity and the microenvironment in advanced non-small cell lung cancer. Nat Commun 2021;12:2540. [Crossref] [PubMed]
77. Simpson KL, Rothwell DG, Blackhall F, et al. Challenges of small cell lung cancer heterogeneity and phenotypic plasticity. Nat Rev Cancer 2025;25:447-62. [Crossref] [PubMed]
78. Remark R, Becker C, Gomez JE, et al. The non-small cell lung cancer immune contexture. A major determinant of tumor characteristics and patient outcome. Am J Respir Crit Care Med 2015;191:377-90.
79. Li Z, Maeda D, Yoshida M, et al. The intratumoral distribution influences the prognostic impact of CD68- and CD204-positive macrophages in non-small cell lung cancer. Lung Cancer 2018;123:127-35. [Crossref] [PubMed]
80. Wu P, Wu D, Zhao L, et al. Inverse role of distinct subsets and distribution of macrophage in lung cancer prognosis: a meta-analysis. Oncotarget 2016;7:40451-60. [Crossref] [PubMed]
81. Jeannin P, Paolini L, Adam C, et al. The roles of CSFs on the functional polarization of tumor-associated macrophages. FEBS J 2018;285:680-99. [Crossref] [PubMed]
82. Ushach I, Zlotnik A. Biological role of granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) on cells of the myeloid lineage. J Leukoc Biol 2016;100:481-9. [Crossref] [PubMed]
83. Van Overmeire E, Stijlemans B, Heymann F, et al. M-CSF and GM-CSF Receptor Signaling Differentially Regulate Monocyte Maturation and Macrophage Polarization in the Tumor Microenvironment. Cancer Res 2016;76:35-42. [Crossref] [PubMed]
84. Owen JL, Torroella-Kouri M, Handel-Fernandez ME, et al. GM-CSF up-regulates the expression of CCL2 by T lymphocytes in mammary tumor-bearing mice. Int J Mol Med 2007;20:129-36.
85. Sierra-Filardi E, Nieto C, Domínguez-Soto A, et al. CCL2 shapes macrophage polarization by GM-CSF and M-CSF: identification of CCL2/CCR2-dependent gene expression profile. J Immunol 2014;192:3858-67. [Crossref] [PubMed]
86. He M, Yu W, Chang C, et al. Estrogen receptor alpha promotes lung cancer cell invasion via increase of and cross-talk with infiltrated macrophages through the CCL2/CCR2/MMP9 and CXCL12/CXCR4 signaling pathways. Mol Oncol 2020;14:1779-1799. [Crossref] [PubMed]
87. Schmall A, Al-Tamari HM, Herold S, et al. Macrophage and cancer cell cross-talk via CCR2 and CX3CR1 is a fundamental mechanism driving lung cancer. Am J Respir Crit Care Med 2015;191:437-47. [Crossref] [PubMed]
88. Wu Y, Yi M, Niu M, et al. Myeloid-derived suppressor cells: an emerging target for anticancer immunotherapy. Mol Cancer 2022;21:184. [Crossref] [PubMed]
89. Solito S, Marigo I, Pinton L, et al. Myeloid-derived suppressor cell heterogeneity in human cancers. Ann N Y Acad Sci 2014;1319:47-65. [Crossref] [PubMed]
90. Bronte V, Brandau S, Chen SH, et al. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat Commun 2016;7:12150. [Crossref] [PubMed]
91. Finke J, Ko J, Rini B, et al. MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy. Int Immunopharmacol 2011;11:856-61. [Crossref] [PubMed]
92. Binsfeld M, Muller J, Lamour V, et al. Granulocytic myeloid-derived suppressor cells promote angiogenesis in the context of multiple myeloma. Oncotarget 2016;7:37931-43. [Crossref] [PubMed]
93. Shi H, Zhang J, Han X, et al. Recruited monocytic myeloid-derived suppressor cells promote the arrest of tumor cells in the premetastatic niche through an IL-1beta-mediated increase in E-selectin expression. Int J Cancer 2017;140:1370-1383. [Crossref] [PubMed]
94. Husain Z, Huang Y, Seth P, et al. Tumor-derived lactate modifies antitumor immune response: effect on myeloid-derived suppressor cells and NK cells. J Immunol 2013;191:1486-95. [Crossref] [PubMed]
95. Grover A, Sanseviero E, Timosenko E, et al. Myeloid-Derived Suppressor Cells: A Propitious Road to Clinic. Cancer Discov 2021;11:2693-706. [Crossref] [PubMed]
96. Chen H, Xu Z, Varner J. Targeting myeloid cells to improve cancer immune therapy. Front Immunol 2025;16:1623436. [Crossref] [PubMed]
97. Lv J, Zhong X, Wang L, et al. Plasticity of myeloid-derived suppressor cells in cancer and cancer therapy. Oncol Res 2025;33:1581-92. [Crossref] [PubMed]
98. Wang S, Fu Y, Ma K, et al. The significant increase and dynamic changes of the myeloid-derived suppressor cells percentage with chemotherapy in advanced NSCLC patients. Clin Transl Oncol 2014;16:616-22. [Crossref] [PubMed]
99. Tian T, Gu X, Zhang B, et al. Increased circulating CD14(+)HLA-DR-/low myeloid-derived suppressor cells are associated with poor prognosis in patients with small-cell lung cancer. Cancer Biomark 2015;15:425-32. [Crossref] [PubMed]
100. Antonia SJ, Mirza N, Fricke I, et al. Combination of p53 cancer vaccine with chemotherapy in patients with extensive stage small cell lung cancer. Clin Cancer Res 2006;12:878-87. [Crossref] [PubMed]
101. Vetsika EK, Koinis F, Gioulbasani M, et al. A circulating subpopulation of monocytic myeloid-derived suppressor cells as an independent prognostic/predictive factor in untreated non-small lung cancer patients. J Immunol Res 2014;2014:659294. [Crossref] [PubMed]
102. Heuvers ME, Muskens F, Bezemer K, et al. Arginase-1 mRNA expression correlates with myeloid-derived suppressor cell levels in peripheral blood of NSCLC patients. Lung Cancer 2013;81:468-74. [Crossref] [PubMed]
103. Liu CY, Wang YM, Wang CL, et al. Population alterations of L-arginase- and inducible nitric oxide synthase-expressed CD11b+/CD14⁻/CD15+/CD33+ myeloid-derived suppressor cells and CD8+ T lymphocytes in patients with advanced-stage non-small cell lung cancer. J Cancer Res Clin Oncol 2010;136:35-45. [Crossref] [PubMed]
104. Feng PH, Lee KY, Chang YL, et al. CD14(+)S100A9(+) monocytic myeloid-derived suppressor cells and their clinical relevance in non-small cell lung cancer. Am J Respir Crit Care Med 2012;186:1025-36. [Crossref] [PubMed]
105. Huang A, Zhang B, Wang B, et al. Increased CD14(+)HLA-DR (-/low) myeloid-derived suppressor cells correlate with extrathoracic metastasis and poor response to chemotherapy in non-small cell lung cancer patients. Cancer Immunol Immunother 2013;62:1439-51. [Crossref] [PubMed]
106. Zhou Q, Tang X, Tian X, et al. LncRNA MALAT1 negatively regulates MDSCs in patients with lung cancer. J Cancer 2018;9:2436-42. [Crossref] [PubMed]
107. Zhang Z, Lin Y, Pan X, et al. Inhibition of non-small cell lung cancer metastasis by knocking down APE1 through regulating myeloid-derived suppressor cells-induced immune disorders. Aging (Albany NY) 2024;16:10435-45. [Crossref] [PubMed]
108. Kohanbash G, McKaveney K, Sakaki M, et al. GM-CSF promotes the immunosuppressive activity of glioma-infiltrating myeloid cells through interleukin-4 receptor-alpha. Cancer Res 2013;73:6413-23. [Crossref] [PubMed]
109. Bronte V, Serafini P, De Santo C, et al. IL-4-induced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. J Immunol 2003;170:270-8. [Crossref] [PubMed]
110. Rodriguez PC, Zea AH, DeSalvo J, et al. L-arginine consumption by macrophages modulates the expression of CD3 zeta chain in T lymphocytes. J Immunol 2003;171:1232-9. [Crossref] [PubMed]
111. Zhao Z, Qin J, Qian Y, et al. FFAR2 expressing myeloid-derived suppressor cells drive cancer immunoevasion. J Hematol Oncol 2024;17:9. [Crossref] [PubMed]
112. Serafini P, Carbley R, Noonan KA, et al. High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells. Cancer Res 2004;64:6337-43. [Crossref] [PubMed]
113. Confino H, Dirbas FM, Goldshtein M, et al. Gaseous nitric oxide tumor ablation induces an anti-tumor abscopal effect. Cancer Cell Int 2022;22:405. [Crossref] [PubMed]
114. Xu J, Luo Y, Yuan C, et al. Downregulation of Nitric Oxide Collaborated with Radiotherapy to Promote Anti-Tumor Immune Response via Inducing CD8+ T Cell Infiltration. Int J Biol Sci 2020;16:1563-74. [Crossref] [PubMed]
115. Juzenaite G, Secklehner J, Vuononvirta J, et al. Lung Marginated and Splenic Murine Resident Neutrophils Constitute Pioneers in Tissue-Defense During Systemic E. coli Challenge. Front Immunol 2021;12:597595.
116. Kargl J, Busch SE, Yang GH, et al. Neutrophils dominate the immune cell composition in non-small cell lung cancer. Nat Commun 2017;8:14381. [Crossref] [PubMed]
117. Sheervalilou M, Ghanei M, Arabfard M. Tumor-associated neutrophils and neutrophil extracellular traps in lung cancer: antitumor/protumor insights and therapeutic implications. Med Oncol 2025;42:266. [Crossref] [PubMed]
118. Eruslanov EB. Phenotype and function of tumor-associated neutrophils and their subsets in early-stage human lung cancer. Cancer Immunol Immunother 2017;66:997-1006. [Crossref] [PubMed]
119. Bodac A, Mayet A, Rana S, et al. Bcl-xL targeting eliminates ageing tumor-promoting neutrophils and inhibits lung tumor growth. EMBO Mol Med 2024;16:158-84. [Crossref] [PubMed]
120. Shaul ME, Fridlender ZG. Tumour-associated neutrophils in patients with cancer. Nat Rev Clin Oncol 2019;16:601-20. [Crossref] [PubMed]
121. Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell 2009;16:183-94. [Crossref] [PubMed]
122. Zhou J, Liu H, Jiang S, et al. Role of tumor-associated neutrophils in lung cancer Oncol Lett 2023;25:2. (Review). [Crossref] [PubMed]
123. Yan L, Borregaard N, Kjeldsen L, et al. The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL. J Biol Chem 2001;276:37258-65.
124. Piccard H, Muschel RJ, Opdenakker G. On the dual roles and polarized phenotypes of neutrophils in tumor development and progression. Crit Rev Oncol Hematol 2012;82:296-309. [Crossref] [PubMed]
125. Coffelt SB, Wellenstein MD, de Visser KE. Neutrophils in cancer: neutral no more. Nat Rev Cancer 2016;16:431-46. [Crossref] [PubMed]
126. He M, Peng A, Huang XZ, et al. Peritumoral stromal neutrophils are essential for c-Met-elicited metastasis in human hepatocellular carcinoma. Oncoimmunology 2016;5:e1219828. [Crossref] [PubMed]
127. Liang W, Li Q, Ferrara N. Metastatic growth instructed by neutrophil-derived transferrin. Proc Natl Acad Sci U S A 2018;115:11060-5. [Crossref] [PubMed]
128. O'Brien S, Thomas RM, Wertheim GB, et al. Ikaros imposes a barrier to CD8+ T cell differentiation by restricting autocrine IL-2 production. J Immunol 2014;192:5118-29. [Crossref] [PubMed]
129. Eruslanov EB, Bhojnagarwala PS, Quatromoni JG, et al. Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer. J Clin Invest 2014;124:5466-80. [Crossref] [PubMed]
130. Singhal S, Bhojnagarwala PS, O'Brien S, et al. Origin and Role of a Subset of Tumor-Associated Neutrophils with Antigen-Presenting Cell Features in Early-Stage Human Lung Cancer. Cancer Cell 2016;30:120-35. [Crossref] [PubMed]
131. Daassi D, Mahoney KM, Freeman GJ. The importance of exosomal PDL1 in tumour immune evasion. Nat Rev Immunol 2020;20:209-15. [Crossref] [PubMed]
132. He G, Zhang H, Zhou J, et al. Peritumoural neutrophils negatively regulate adaptive immunity via the PD-L1/PD-1 signalling pathway in hepatocellular carcinoma. J Exp Clin Cancer Res 2015;34:141. [Crossref] [PubMed]
133. Wang TT, Zhao YL, Peng LS, et al. Tumour-activated neutrophils in gastric cancer foster immune suppression and disease progression through GM-CSF-PD-L1 pathway. Gut 2017;66:1900-11. [Crossref] [PubMed]
134. Cheng Y, Li H, Deng Y, et al. Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma. Cell Death Dis 2018;9:422. [Crossref] [PubMed]
135. Zhan Y, Lew AM, Chopin M. The Pleiotropic Effects of the GM-CSF Rheostat on Myeloid Cell Differentiation and Function: More Than a Numbers Game. Front Immunol 2019;10:2679. [Crossref] [PubMed]
136. Ozakinci H, Song X, Nazario GS, et al. Rapid Autopsy to Define Dendritic Cell Spatial Distribution and T Cell Association in Lung Adenocarcinoma. J Immunol 2024;213:1033-41. [Crossref] [PubMed]
137. Rodriguez LIL, Amadio R, Piperno GM, et al. Tissue-specific properties of type 1 dendritic cells in lung cancer: implications for immunotherapy. J Immunother Cancer 2025;13:e010547. [Crossref] [PubMed]
138. Zhu M, Wang B, Zhang X, et al. Assessment of baseline CCL19(+) dendritic cell infiltration for predicting responses to immunotherapy in lung adenocarcinoma patients. Nan Fang Yi Ke Da Xue Xue Bao 2024;44:1529-1536. [Crossref] [PubMed]
139. Suzuki Y, Yanagawa H, Nishioka Y, et al. Efficient generation of dendritic cells from alveolar and pleural macrophages as well as blood monocytes in patients with lung cancer. Lung Cancer 2001;34:195-205. [Crossref] [PubMed]
140. Drings P, Fischer JR. Biology and clinical use of GM-CSF in lung cancer. Lung 1990;168:1059-68. [Crossref] [PubMed]
141. Erkisi M, Erkurt E, Zeren H, et al. Anticipated administration of GM-CSF in the treatment of non small cell lung cancer. J Exp Clin Cancer Res 2001;20:345-9.
142. Hamm J, Schiller JH, Cuffie C, et al. Dose-ranging study of recombinant human granulocyte-macrophage colony-stimulating factor in small-cell lung carcinoma. J Clin Oncol 1994;12:2667-76. [Crossref] [PubMed]
143. Rao RD, Anderson PM, Arndt CA, et al. Aerosolized granulocyte macrophage colony-stimulating factor (GM-CSF) therapy in metastatic cancer. Am J Clin Oncol 2003;26:493-8. [Crossref] [PubMed]
144. Qiu Y, He X, Li Z, et al. Efficacy of early combination of local radiotherapy and GM-CSF for advanced non-small cell lung cancer treated with icotinib. Ir J Med Sci 2020;189:791-7. [Crossref] [PubMed]
145. Kong Y, Zhao X, Xu M, et al. PD-1 Inhibitor Combined With Radiotherapy and GM-CSF (PRaG) in Patients With Metastatic Solid Tumors: An Open-Label Phase II Study. Front Immunol 2022;13:952066. [Crossref] [PubMed]
146. Ni J, Wang X, Wu L, et al. Sintilimab in combination with stereotactic body radiotherapy and granulocyte-macrophage colony-stimulating factor in metastatic non-small cell lung cancer: The multicenter SWORD phase 2 trial. Nat Commun 2024;15:7242. [Crossref] [PubMed]
147. Guerrero P, Bono C, Sobén M, et al. GM-CSF receptor expression determines opposing innate memory phenotypes at different stages of myelopoiesis. Blood 2024;143:2763-77. [Crossref] [PubMed]
148. Kamata N, Kutsuna H, Hato F, et al. Activation of human neutrophils by granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha: role of phosphatidylinositol 3-kinase. Int J Hematol 2004;80:421-7. [Crossref] [PubMed]
149. Dijkers PF, van Dijk TB, de Groot RP, et al. Regulation and function of protein kinase B and MAP kinase activation by the IL-5/GM-CSF/IL-3 receptor. Oncogene 1999;18:3334-42. [Crossref] [PubMed]
150. Klein JB, Rane MJ, Scherzer JA, et al. Granulocyte-macrophage colony-stimulating factor delays neutrophil constitutive apoptosis through phosphoinositide 3-kinase and extracellular signal-regulated kinase pathways. J Immunol 2000;164:4286-91. [Crossref] [PubMed]
151. Yue M, Qin Z, Tang S, et al. Concurrent PIK3CA mutant promotes cachexia through inflammatory signaling in EGFR mutant lung cancer. Nat Commun 2025;17:704. [Crossref] [PubMed]
152. Tan RB, Yap YH. Talimogene Laherparepvec (T-VEC): Expanding Horizons in Oncolytic Viral Therapy Across Multiple Cancer Types. Anticancer Agents Med Chem 2026;26:175-85. [Crossref] [PubMed]
153. Barker CA, D'Angelo SP, Wasilewski G, et al. A phase II randomized trial of talimogene laherparepvec oncolytic immunotherapy with or without radiotherapy for patients with cutaneous metastases from solid tumors. Radiother Oncol 2024;200:110478. [Crossref] [PubMed]