M2-polarized tumor-associated macrophages as key orchestrators of gastric cancer pathogenesis and therapeutic resistance

Abstract

This article systematically reviews the central role of M2 tumor-associated macrophages (M2-TAMs) in the tumor microenvironment of gastric cancer. M2-TAMs originate from circulating monocytes, which are recruited by tumor chemokines and polarized into a pro-tumor phenotype under the influence of factors such as IL-4 and IL-10. They can be further divided into functionally cooperative subtypes M2a, M2b, M2c, and M2d, each playing distinct roles in the initiation and progression of gastric cancer: activating key signaling pathways such as PI3K/Akt/mTOR and JAK/STAT3 through cytokine secretion, and utilizing exosomes to deliver functional non-coding RNAs that directly promote tumor cell proliferation, invasion, and survival; driving angiogenesis and lymphangiogenesis by secreting factors such as VEGF, thus paving the way for the growth and metastasis of gastric malignant tumors; constructing a robust immunosuppressive microenvironment by highly expressing PD-L1, secreting inhibitory cytokines, and recruiting regulatory T cells, thereby mediating immune escape; promoting glycolysis and lactate metabolism, forming a self-reinforcing metabolic-immunosuppressive axis with tumor cells; In addition, they promote metastasis and contribute to chemotherapy and immunotherapy resistance through complex interactions with cancer cells and fibroblasts at specific metastatic sites such as the peritoneum and liver. Based on their pivotal position, strategies targeting M2-TAMs, such as blocking their recruitment, repolarizing them to an anti-tumor phenotype, or inhibiting their function, have become a highly promising new direction for therapy. Future research needs to further elucidate their heterogeneity and, through rational clinical trial design, promote the combination of these strategies with existing therapies, aiming to fundamentally improve the treatment landscape of gastric cancer.

Introduction

Gastric cancer (GC) remains a significant global health burden, with approximately 990,000 new cases and 738,000 deaths annually. Despite declining incidence and improved survival for early-stage disease, advanced GC continues to have a dismal prognosis, with a 5-year survival rate < 30% [1]. Historically, cancer research focused predominantly on the intrinsic properties of tumor cells. However, the paradigm has now decisively shifted towards understanding the tumor microenvironment (TME), a dynamic and orchestrated ecosystem that co-evolves with the tumor [2, 3]. Within this complex milieu, non-neoplastic cells, particularly immune cells, are recognized as critical regulators of tumor fate. Among these, tumor-associated macrophages (TAMs) have emerged as pivotal players.M2-TAMs, with their anti-inflammatory and immunosuppressive phenotypes, dominate the TME and contribute to multiple aspects of tumor progression [4]. These macrophages are involved in promoting tumor angiogenesis, suppressing the activity of other immune cells, stimulating tumor cell proliferation and migration, and facilitating the immune escape of gastric cancer [5]. Given their critical role in these processes, understanding the mechanisms by which M2-TAMs regulate gastric cancer progression is crucial for the development of new therapeutic strategies aimed at targeting these cells. While recent reviews have provided broad overviews of the tumor microenvironment (TME) in gastric cancer (GC), this article offers a focused and updated perspective on the “M2-polarized tumor-associated macrophage (M2-TAM) subset”. Distinct from prior publications, we meticulously synthesize the most recent evidence (2023–2024) elucidating how M2-TAMs orchestrate GC progression through novel exosomal networks (e.g., circRNA_102191, circGLIS3) and metabolic reprogramming via lactate and glycolysis. Furthermore, a significant portion of this review is dedicated to emerging therapeutic strategies that aim to “deplete, repolarize, or disrupt the function of M2-TAMs”, with a critical analysis of drugs in preclinical and clinical development (e.g., DKN-01, CMA-R848 nano-micelles). By integrating these cutting-edge mechanisms and translational prospects, this review not only consolidates current knowledge but also identifies promising, targetable nodes for overcoming therapy resistance in GC (Fig. 1).

Fig. 1.

Relationship between M2-TAM infiltration and clinical outcomes in gastric cancer using TCGA data. A Immune cell infiltration profile generated by CIBERSORT algorithm, showing a high proportion of M2 macrophages. B Kaplan-Meier survival analysis of patients stratified by high vs. low M2-TAM infiltration levels (cut-off: median). Log-rank test was used for statistical comparison. C Gene Set Enrichment Analysis (GSEA) plots showing significant enrichment of biological processes related to macrophage activation and function. D KEGG pathway enrichment analysis of differentially expressed genes; the top 10 significantly enriched pathways are displayed.2. Origin and Functional Significance of M2-TAMs in Gastric Cancer

Origin and functional significance of M2-TAMs in gastric cancer

M2-TAMs, also known as tumor-associated macrophages (TAMs), are critical immune cells within TME of gastric cancer. These macrophages originate from circulating monocytes, which are recruited to the TME by signals released from tumor cells, such as chemokines and cytokines. Initially, tissue-resident macrophages, differentiated from embryonic hematopoietic stem cells, dominate the TME in early stages of cancer development [6]. However, as tumors progress, monocytes, particularly those expressing Ly6⁺ CCR2⁺ markers, are recruited to the TME where they differentiate into TAMs, predominantly adopting an M2 phenotype [7]. The polarization of macrophages into the M2 subtype is influenced by several factors in the TME, including the presence of cytokines such as IL-4, IL-10, and TGF-β [8]. These M2-TAMs have anti-inflammatory and immunosuppressive properties, which allow them to promote tumor growth by creating an immune-suppressive microenvironment. This shift in macrophage polarization not only supports tumor progression but also contributes to the complex interactions within the TME that enhance cancer cell survival, migration, and metastasis. In gastric cancer, M2-TAMs play a central role in facilitating carcinogenesis and tumor progression. These macrophages contribute to several key aspects of tumor biology, including tumor cell proliferation, immune evasion, angiogenesis, and chemoresistance. One of the major mechanisms by which M2-TAMs promote tumor growth is through the activation of pro-tumorigenic signaling pathways such as the PI3K/Akt and JAK/STAT3 pathways. These pathways are involved in promoting cell proliferation, survival, and migration by modulating gene expression related to cell cycle regulation and apoptosis resistance. Additionally, M2-TAMs also enhance tumor angiogenesis by secreting pro-angiogenic factors such as VEGF (vascular endothelial growth factor) and MMPs [9, 10]. These factors promote the formation of new blood vessels that supply nutrients and oxygen to rapidly growing tumors, supporting their continued expansion and metastasis. The secretion of IL-6 and other cytokines by M2-TAMs further exacerbates the inflammatory environment, thereby contributing to tumor progression and metastasis [11]. Moreover, M2-TAMs have been implicated in the evasion of the anti-tumor immune response. They achieve this by expressing immune checkpoint molecules like PD-L1, which inhibit the activation of cytotoxic T cells [12]. This immunosuppressive effect further hinders the host’s immune system from effectively targeting and eliminating tumor cells. By actively suppressing immune surveillance, M2-TAMs help gastric cancer cells escape immune-mediated destruction, facilitating cancer progression and resistance to therapies.

In the evolutionary progression of gastric cancer, M2-TAMs play a crucial role in tumor growth and metastasis. Takaishi et al. were the first to identify gastric cancer stem cells (GCSCs) from gastric cancer cells [13]. These cells can differentiate into various functional cell types required by the stomach through progenitor cells and rapidly transform into GCSCs under oncogenic stimuli, thereby promoting gastric carcinogenesis. Existing studies on the relationship between GCSCs and M2-TAMs reveal that GCSCs influence the immune microenvironment of gastric cancer by recruiting TAMs, which in turn provide a supportive ecological niche for GCSCs, enhancing their invasion and metastasis [14, 15].

In summary, M2-TAMs are not only pivotal in promoting gastric cancer progression but also play a critical role in immune evasion, angiogenesis, and the establishment of a tumor-supportive microenvironment. Their complex interactions with tumor cells and other immune cells make them a central focus for therapeutic strategies aimed at targeting macrophage polarization or inhibiting their pro-tumorigenic functions. Understanding the origins and functional significance of M2-TAMs in gastric cancer is essential for the development of novel immunotherapies that can effectively modulate TME and improve patient outcomes (Fig. 2).

Fig. 2.

The role of CCL-2 chemokine signaling in monocyte recruitment and tumor-associated macrophage polarization

In the gastric cancer tumor microenvironment, the CCL-2-dominated chemokine signaling pathway orchestrates monocyte recruitment from the bone marrow to the tumor site. Under the influence of cytokines such as TGF-β, IL-10 and IFN-α, these recruited monocytes further differentiate into functionally distinct M1- or M2-type tumor-associated macrophages (TAMs). Notably, the tumor-promoting M2-type TAMs are not a homogeneous group; based on the stimulation signals they receive, they can be further subdivided into four functional subtypes—M2a, M2b, M2c and M2d—each playing a distinct yet synergistic role in gastric cancer progression. Specifically, the M2a subtype, primarily induced by IL-4 or IL-13 [16], establishes an immunosuppressive microenvironment through high expression of CD206 and arginase 1, and by secreting chemokines that recruit regulatory T cells and participate in tissue remodeling [17, 18]. The M2b subtype, inducible by immune complexes together with TLR agonists, can co-produce both pro-inflammatory and anti-inflammatory factors, thereby potentially regulating the balance between inflammation and immunosuppression in gastric cancer [19]. The M2c subtype, mainly induced by IL-10 and TGF-β, acts as a potent immunosuppressive subset characterized by high expression of the scavenger receptor CD163 and abundant secretion of inhibitory factors. The M2d subtype, induced by factors such as adenosine, is distinguished by its efficient secretion of VEGF, playing a prominent role in promoting tumor angiogenesis. Together, these M2-TAMs drive gastric cancer deterioration through a series of core mechanisms: they directly stimulate tumor cell proliferation by activating key signaling pathways such as PI3K/Akt/mTOR and JAK/STAT3; induce tumor neovascularization by secreting potent pro-angiogenic factors like VEGF; mediate immune escape by expressing immune-checkpoint ligands such as PD-L1 and secreting inhibitory cytokines that directly suppress effector T-cell function; and further enhance tumor cell chemotherapy resistance through the secretion of protective factors and the delivery of exosomes. Ultimately, a self-reinforcing positive-feedback loop forms between gastric cancer cells and TAMs: gastric cancer cells continuously secrete various inflammatory factors, chemokines and signaling molecules that shape TAM polarization and function; in turn, the activated M2-TAMs further promote tumor proliferation, invasion, angiogenesis and immune escape through the aforementioned mechanisms, collectively driving disease progression.

Roles of M2-polarized macrophages in the pathogenesis of gastric cancer

Promoting gastric cancer cell proliferation and invasion

M2-polarized tumor-associated macrophages (M2-TAMs) serve as central regulators within the gastric cancer microenvironment. They drive the proliferation, survival, metastasis, and therapy resistance of gastric cancer cells through three interconnected and mutually reinforcing mechanisms: signaling pathway activation mediated by secreted factors, exosome-mediated intercellular communication, and metabolic reprogramming. Specifically: First, at the level of secreted factors, M2-TAMs release various cytokines and chemokines that directly activate multiple key pro-survival and proliferative pathways within gastric cancer cells. For example, the CXC motif chemokine ligand 5 (CXCL5) secreted by M2-TAMs activates the PI3K/Akt/mTOR pathway, thereby enhancing gastric cancer cell resistance to 5-fluorouracil (5-FU) chemotherapy [20]. The detailed molecular mechanism of this pathway involves PI3K phosphorylation of PIP2 to generate PIP3, which subsequently activates Akt and mTOR, promoting cell cycle progression [21, 22]. Simultaneously, IL-6 secreted by M2-TAMs activates the JAK/STAT3 pathway, leading to STAT3 phosphorylation, dimerization, and nuclear translocation, which upregulates the expression of pro-proliferation and anti-apoptotic genes such as Bcl-2, cyclin D1, and c-Myc [23–28]. Additionally, CD204-positive M2-like TAMs secrete tumor necrosis factor-alpha (TNF-α), which upregulates miR-210 in gastric cancer cells via the NF-κB/HIF-1α signaling pathway, thereby suppressing the expression of its target, netrin-4 (NTN4), and promoting cell migration [29].Second, regarding exosome-mediated communication, a complex bidirectional molecular dialogue exists between M2-TAMs and gastric cancer cells. On one hand, exosomes derived from M2-TAMs deliver functional non-coding RNAs to gastric cancer cells to reprogram their function: for instance, the exosome-enriched long non-coding RNA (lncRNA) MALAT1, upon entering gastric cancer cells, both stabilizes δ-catenin protein to inhibit its degradation and acts as a molecular sponge for miR-217-5p to upregulate hypoxia-inducible factor-1α (HIF-1α) expression [30]. The synergistic activation of the β-catenin and HIF-1α signaling pathways collectively enhances aerobic glycolysis (i.e., the Warburg effect) in gastric cancer cells, promoting proliferation and chemotherapy resistance [30]. This mechanism is also described as activating the β-catenin signaling pathway to upregulate HIF-1α and stimulate glycolysis [30]. Furthermore, exosome-delivered miR-21 from M2-TAMs inhibits the tumor suppressor gene PTEN, thereby activating the PI3K/Akt signaling pathway to promote cancer cell growth [31]. On the other hand, exosomes derived from gastric cancer cells (e.g., those encapsulating pyruvate kinase M2, PKM2) can be taken up by macrophages, inducing their polarization towards the M2 phenotype and forming a positive feedback loop that amplifies pro-tumor effects [32].Finally, in terms of metabolic reprogramming, M2-TAMs produce and secrete lactate through aerobic glycolysis. This not only provides ATP and biosynthetic precursors for rapidly proliferating tumor cells [33, 34] but can also activate signaling pathways such as histone acetylation, thereby enhancing the expression of pro-proliferation genes [35]. Concurrently, the β-catenin/HIF-1α pathway, activated by exosomal lncRNA MALAT1 and others, further stimulates glycolytic metabolism, forming a feedback loop that simultaneously amplifies cancer cell proliferation and macrophage M2 polarization [30].

In summary, these intertwined mechanisms—activating multiple signaling pathways like PI3K/Akt/mTOR and JAK/STAT3 through secreted factors, facilitating the bidirectional exchange of genetic material including non-coding RNAs via exosomes, and remodeling the tumor metabolic environment to support the Warburg effect—collectively constitute a robust pro-tumor microenvironmental network. This network serves as a crucial foundation for the development, progression, and therapy resistance of gastric cancer [31].

Promoting angiogenesis and lymphangiogenesis

M2-polarized tumor-associated macrophages (M2-TAMs) are central drivers of angiogenesis and lymphangiogenesis in gastric cancer. They remodel the tumor microenvironment by secreting key factors, activating relevant signaling pathways, and interacting with tumor cells to support tumor growth, invasion, and metastasis.

In angiogenesis, M2-TAMs secrete a series of pro-angiogenic factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and matrix metalloproteinases (MMPs). VEGF directly stimulates endothelial cell proliferation, migration, and lumen formation, and its high expression is closely associated with increased microvessel density and poor prognosis in gastric cancer [36]. Simultaneously, M2-TAMs (such as CD163-positive subsets) can upregulate MMP-2 expression and downregulate its inhibitor TIMP-3 in gastric cancer cells, thereby degrading the extracellular matrix (ECM) and facilitating angiogenesis and tumor cell invasion [37]. This process is precisely regulated by key signaling pathways: on one hand, factors like IL-4 and IL-13 secreted by M2-TAMs can activate the PI3K/Akt/mTOR pathway in endothelial and tumor cells, directly promoting angiogenesis [38]; on the other hand, cytokines like IL-6 secreted by them activate the STAT3 signaling pathway, thereby inducing the expression of pro-angiogenic factors such as VEGF and MMPs [39].Furthermore, the upregulated PLXDC2 protein in M2-TAMs can enhance angiogenesis by regulating epithelial-mesenchymal transition (EMT) and directly promoting endothelial cell migration [40]; the IL-8 they release also serves as a potent chemokine stimulating neovascularization [23]. Beyond classical angiogenesis, M2-TAMs may indirectly promote “vascular mimicry”—where tumor cells themselves form channel networks—by driving EMT in gastric cancer cells [41], thereby further supporting tumor blood supply.In lymphangiogenesis, M2-TAMs promote lymphatic vessel neogenesis by secreting lymphangiogenic factors such as VEGF-C and VEGF-D and by directly stimulating lymphatic endothelial cells. This process represents a key step in gastric cancer lymph node metastasis, a mechanism already confirmed in other cancers (e.g., non-small cell lung cancer) [42]. Notably, M2-TAMs play a crucial role in gastric cancer peritoneal metastasis via the greater omentum “milky spots.” Studies show that inhibiting macrophage polarization towards the M2 phenotype in “milky spots” (e.g., by PTX3 inhibiting JNK1/2 phosphorylation, thereby reducing IL-4 and IL-10 expression) can effectively suppress metastasis [43], providing indirect evidence for the promoting role of M2-TAMs in this lymphatic metastasis route.

In summary, M2-TAMs coordinately drive angiogenesis and lymphangiogenesis through multiple factors and pathways, not only providing nutrients for the tumor but also opening metastasis channels and forming a vicious cycle. Therefore, targeting this process represents a potential strategy to inhibit gastric cancer progression.

Inducing tumor cell immune escape

Within the gastric cancer immune microenvironment, M2-polarized tumor-associated macrophages (M2-TAMs) function as core regulators that establish immunosuppression, drive immune escape, and correlate with poor prognosis [44, 45]. They exert their central role by potently suppressing key anti-tumor immune responses—primarily those mediated by CD8 + T cells—through multiple interrelated mechanisms. First, M2-TAMs constitute a fundamental basis for gastric cancer cell resistance to T cell-mediated cytotoxicity. Research indicates that quiescent cancer cells (QCCs) enriched with M2-TAMs represent a core mechanism of immune resistance [46]. In vivo models demonstrate that high M2-TAM infiltration exhibits a significant negative correlation with CD8 + T cell numbers and ranks among the strongest factors suppressing T cell effector functions [47]. This suppression occurs partially through immune checkpoint interactions: M2-TAMs highly express programmed death-ligand 1 (PD-L1), which directly inhibits T cell activation and proliferation upon binding to PD-1 on T cells [48]. Concurrently, M2-TAMs can promote PD-L1 upregulation on tumor cells themselves by secreting factors such as transforming growth factor-beta (TGF-β), thereby further mediating immune escape [49].Second, M2-TAMs actively shape an inhibitory microenvironment to exclude and exhaust T cells. They recruit regulatory T cells (Tregs) via the CXCL12-CXCR4 signaling pathway, indirectly impairing T cell function [50], and secrete immunosuppressive factors including granulysin and IL-10, which inhibit the recruitment and distribution of CD8 + T cells at the tumor site, resulting in “T cell exclusion” [12]. Furthermore, gastric cancer cells can activate the PI3K/AKT/mTORC2 pathway by secreting factors like legumain (LGMN), thereby driving macrophage M2 polarization and metabolic reprogramming, leading to anti-PD-1 therapy resistance [51]. Exosome-mediated intercellular communication represents another critical pathway. Exosomes derived from M2-TAMs can carry long non-coding RNAs (e.g., NEAT1) that promote CD8 + T cell apoptosis by regulating the miR-101-3p/ZEB1/PD-L1 axis [52]. Alternatively, they can help tumor cells evade recognition and attack by cytotoxic T lymphocytes (CTLs) by downregulating MHC-I molecule expression on tumor cell surfaces [53, 54]. Physicochemical cues within the tumor microenvironment (TME) also modulate this process; for instance, electrical stimulation may exacerbate IL-4-induced M2 polarization [55, 56], whereas targeting ion channels (e.g., KCa3.1) can block IL-10-induced immune escape [57]. Based on these mechanisms, targeting M2-TAMs has emerged as a viable strategy to enhance immunotherapy efficacy. On one hand, existing drug combinations (e.g., anti-PD-1 antibody combined with Regorafenib) can synergistically enhance CD8 + T cell activity by reducing TAMs and activating interferon pathways [58]. On the other hand, novel intervention strategies are under exploration, including using Dextran Sulfate to inhibit M2 polarization and lower PD-L1 expression [59], employing nanocarriers to deliver Toll-like receptor agonists (e.g., Resiquimod) or supramolecular peptides (SPADS) to reprogram M2-TAMs into anti-tumor M1 phenotypes [60, 61], and developing nanocomplexes that simultaneously inhibit exosome release and block M2 differentiation [62].

In summary, M2-TAMs construct a formidable immunosuppressive fortress through multiple concerted mechanisms: directly inhibiting T cell function, recruiting and activating other inhibitory cells, secreting immunosuppressive factors, and facilitating exosome-mediated signal transmission. Consequently, disrupting the dynamic interactions between M2-TAMs and T cells represents a promising approach to reverse immunosuppression and improve the efficacy of gastric cancer immunotherapy.

Involvement in tumor metabolic reprogramming

M2-type tumor-associated macrophages (TAMs) profoundly influence gastric cancer cell energy acquisition and utilization by reshaping the metabolic landscape of the tumor microenvironment, thereby driving tumor progression. Metabolic reprogramming serves as a key prerequisite for TAM polarization toward the M2 phenotype—a process intricately intertwined with the metabolic demands of tumor cells [63]. In gastric cancer, M2 macrophages enhance tumor cell energy metabolism by promoting aerobic glycolysis. Studies demonstrate that enhanced glycolytic characteristics in gastric cancer cells closely associate with the M2 macrophage phenotype [64]. This heightened glycolytic flux generates substantial lactate, which functions not merely as a glycolysis end-product but also as a critical immunosuppressive mediator. Tumor cell-secreted lactate can polarize macrophages toward the M2 phenotype via the monocarboxylate transporter (MCT)-HIF1α signaling axis [64]. This “lactate-MCT-HIF1α” axis constitutes a key signaling cascade that links gastric cancer cell metabolic reprogramming to macrophage polarization, establishing a self-reinforcing metabolic-immune regulatory loop.Exosomes, as vital carriers of intercellular communication, also participate in this metabolic regulatory network. For example, exosomes derived from gastric cancer cells can encapsulate key metabolic proteins such as PKM2 (pyruvate kinase M2) and deliver them to macrophages, inducing their differentiation into the M2 phenotype and thereby promoting gastric cancer progression [32]. This exosome-mediated metabolic reprogramming enables tumor cells to remotely “educate” immune cells, fostering an immunosuppressive microenvironment conducive to their growth.Non-coding RNAs and other molecules carried by exosomes play significant roles in regulating tumor glycolysis and progression. For instance, exosome-derived long non-coding RNAs like metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) can promote tumor glycolytic metabolism and malignant progression by regulating key signaling pathways, including β-catenin and HIF-1α [65]. HIF-1α, a core transcription factor for cellular adaptation to hypoxia, upregulates a series of glycolysis-related genes upon stabilization, driving the Warburg effect. Within the gastric cancer microenvironment, tumor cells transfer molecules such as MALAT1 via exosomes to macrophages or neighboring tumor cells, thereby stabilizing HIF-1α, enhancing glycolytic flux, and promoting M2 macrophage polarization. This exosome-mediated, non-coding RNA-based metabolic reprogramming constitutes a sophisticated dialogue mechanism between tumor cells and their microenvironment.Single-cell analysis further reveals metabolic reprogramming-based mutual communication between tumor cells and macrophages in gastric cancer. Research indicates that gastric cancer cells with high epithelial-mesenchymal transition (EMT) scores and stem-like features exhibit elevated glycosaminoglycan metabolism and engage in bidirectional communication with macrophages via ligands such as RPS19. This interaction leads to the expression reprogramming of genes like HS6ST2 and SERPINE1, correlating with poor patient prognosis [66]. These findings suggest that the state of malignant stem-like/EMT tumor cells may be co-regulated by tumor cell-macrophage intercommunication and metabolic reprogramming within the TME.Lactate, a core glycolytic metabolite, occupies a central position in inducing M2 polarization and forming a metabolic-immune regulatory axis. The vigorous glycolysis of gastric cancer cells produces and secretes large quantities of lactate, which serves not only as metabolic waste but also as an important signaling molecule [67]. After entering macrophages via MCTs, lactate can induce their polarization toward the immunosuppressive M2 phenotype. Notably, this polarizing effect operates independently of downstream mitochondrial metabolism following lactate entry, as genetic studies demonstrate that knocking out the mitochondrial pyruvate carrier (MPC) to block lactate mitochondrial import does not affect IL-4/lactate-induced macrophage polarization. This suggests that lactate molecules themselves or the epigenetic modifications they induce, such as histone lactylation, may be key drivers of polarization [68]. M2-type macrophages subsequently secrete anti-inflammatory factors like IL-10, further inhibiting T cell function while promoting angiogenesis and tissue remodeling, thereby accelerating tumor progression [67]. Additionally, lactate can stimulate M2-type TAMs to secrete IL-6 in cancers such as endometrial cancer, promoting tumor cell invasion and metastasis [69]. Therefore, targeting the lactate metabolic axis—for example, using lactate oxidase (LOX) to oxidize tumor-secreted lactate or employing MCT inhibitors—has proven effective in reversing M2 polarization and enhancing anti-tumor immunity [70].

In summary, M2-type TAMs deeply engage in gastric cancer metabolic reprogramming by promoting glycolysis, transmitting exosomal signal molecules, and responding to lactate metabolites. This involvement establishes a self-sustaining, lactate-centric metabolic-immunosuppressive axis, providing a theoretical foundation for developing novel therapeutic strategies targeting this axis.

Role in specific metastatic microenvironments

Gastric cancer metastasis, particularly to the peritoneum and liver, constitutes a unique and highly heterogeneous ecosystem. Within this system, M2-polarized tumor-associated macrophages (TAMs) drive metastatic foci formation and therapy resistance through complex intercellular communication and specific signaling axes.In the peritoneal metastasis microenvironment, extracellular vesicles (EVs) derived from gastric cancer cells play a pivotal role. Studies show that EVs purified from gastric cancer cells or malignant ascites can differentiate peripheral blood monocyte-derived macrophages into M2-like phenotypes, characterized by morphological alterations and CD163/206 expression [49]. These gastric cancer EV-differentiated macrophages, in turn, enhance the migratory capacity of gastric cancer cells, a process in which STAT3 protein carried by the EVs may participate [71]. This EV-mediated macrophage reprogramming represents part of the potential mechanism underlying intraperitoneal cancer microenvironment formation.Furthermore, peritoneal metastases frequently accompany fibrosis, and interactions between cancer-associated fibroblasts (CAFs) and gastric cancer cells further mold the immunosuppressive microenvironment. For instance, gastric cancer cell-conditioned medium can augment CXCL12 expression in fibroblast-like cell line LmcMF, thereby stimulating M2 macrophage migration. Conversely, the drug Tranilast can inhibit M2 macrophage migratory ability by suppressing CXCL12 secretion from CAFs [72]. In vivo models demonstrate that inhibiting CAF function can ameliorate the immunosuppressive microenvironment, promote CD8 + T lymphocyte infiltration, and induce cancer cell apoptosis [73]. These findings reveal intricate crosstalk among gastric cancer cells, CAFs, and M2 TAMs within the peritoneal metastasis ecosystem, collectively propelling immune escape and metastasis.In the liver metastasis microenvironment, M2 TAMs similarly fulfill a core pro-metastatic function. Single-cell sequencing and clinical sample analyses reveal abnormally high expression of RNA acetyltransferase NAT10 in liver-metastatic gastric cancer cells [73]. NAT10 promotes CXCL2 secretion by mediating N4-acetylcytidine modification of CXCL2 mRNA to enhance its stability. The secreted CXCL2 subsequently drives the infiltration and polarization of M2-like macrophages; these polarized macrophages produce oncostatin M, which transcriptionally activates NAT10 expression via the STAT3 signaling pathway, establishing a positive feedback loop that collectively promotes gastric cancer liver metastasis [73]. Additionally, another study focusing on the EFNB2-EPHB2 axis found that EFNB2-expressing TAMs interact with EPHB2-expressing tumor cells, disrupting the tumor cells’ circadian rhythm and activating downstream signaling. This interaction promotes liver metastasis by enhancing the Warburg effect in metastatic foci [74]. These discoveries underscore that, within specific metastatic organs like the liver, precise dialogue between tumor cells and M2 TAMs via particular signaling molecules (e.g., CXCL2, EFNB2) is crucial for forming a pro-metastatic ecosystem.The development of these specific metastatic microenvironments often closely associates with primary immunotherapy resistance. For example, microenvironments composed of specific cell subpopulations such as SPP1 + TAMs and THBS2 + CAFs may drive resistance through signaling axes analogous to C3-C3AR1 [21]. Although the provided references do not directly address the C3-C3AR1 axis, other revealed signaling pathways offer a pertinent analogy. Research indicates that soluble legumain (sLGMN) secreted by gastric cancer cells binds to integrin αvβ3 on macrophage surfaces, activating the PI3K/AKT/mTORC2 signaling pathway, promoting metabolic reprogramming, and polarizing macrophages from M1 to M2 phenotype [51]. This sLGMN/integrin αvβ3/PI3K/AKT/mTORC2 axis fosters immune escape in gastric cancer and confers resistance to anti-PD-1 immunotherapy [51]. Similarly, within the context of chemotherapy resistance, crosstalk between M2-polarized macrophages and gastric cancer cells promotes chemoresistance via the CXCL5/PI3K/AKT/mTOR pathway [75]. These mechanisms suggest that in metastatic foci, M2 TAMs and stromal cells (e.g., CAFs), interconnected by specific signaling axes (such as sLGMN/integrin αvβ3 and CXCL5), co-construct a highly immunosuppressive and therapy-resistant microenvironment. This enables metastatic lesions to evade therapeutic attacks and sustain progression.

Therefore, in-depth analysis of the functions and interaction networks among cell subpopulations within these specific metastatic ecosystems is paramount for devising new strategies to target metastatic foci and overcome therapy resistance.

Mechanisms by which M2-polarized macrophages promote chemotherapy resistance

M2-polarized tumor-associated macrophages (M2-TAMs) significantly enhance gastric cancer cell resistance to chemotherapy agents (including 5-fluorouracil, cisplatin, and oxaliplatin) and other anti-tumor therapies through a complex network encompassing key signaling pathway activation, exosome-mediated non-coding RNA transfer, cytokine secretion, and metabolic reprogramming. Their core mechanisms operate through the following interrelated dimensions: First, M2-TAMs activate central pro-survival signaling pathways within tumor cells by secreting specific factors. Notably, secreted CXC motif chemokine ligand 5 (CXCL5) directly bolsters gastric cancer cell survival, anti-apoptotic capacity, and 5-fluorouracil (5-FU) resistance by activating the PI3K/Akt/mTOR pathway [76]. This process establishes a crucial positive feedback loop: activated PI3K/AKT/mTOR signaling not only impacts tumor cells but also promotes monocyte polarization toward the M2 phenotype. The newly polarized M2-TAMs, in turn, secrete additional CXCL5, thereby perpetuating and intensifying resistance. Clinical sample analysis further corroborates that high CXCL5 expression in gastric cancer tissues significantly correlates with elevated infiltration of CD163+/CD206 + M2 macrophages and reduced overall patient survival [76]. Beyond CXCL5, M2-TAM subsets (e.g., M2-1 and M2-2) interact with other cells (such as neutrophils) to secrete cytokines including oncostatin M (OSM) and IL-1β. These cytokines activate JAK/STAT and MAPK pathways and consolidate M2 polarization via STAT3 phosphorylation, collectively augmenting resistance [77, 78]. The cytokine IL-4 induces macrophage metabolic reprogramming by upregulating the PI3K/Akt/mTOR pathway, enhancing glycolysis, fostering an acidic microenvironment, and increasing FcγRIIB expression on M2-TAMs, thereby supporting chemoresistance [55]. Moreover, Helicobacter pylori (Hp) stimulation or Yes-associated protein 1 (YAP1) overexpression can prompt gastric cancer cells to secrete IL-6 or IL-3, respectively. These secretions drive M2 polarization, establish positive feedback loops, and subsequently enhance resistance by activating pathways like JAK/STAT3 [79–81]. Second, exosomes serve as pivotal intercellular communication vehicles that directly confer drug resistance to gastric cancer cells by delivering diverse non-coding RNAs (ncRNAs). This represents a prevalent and efficient mechanism of M2-TAM action. For instance, exosomes derived from M2-TAMs can transfer circular RNA circ_0008253 to heighten gastric cancer cell resistance to oxaliplatin (OXA) [82]; deliver miR-588 to promote cisplatin (DDP) resistance by targeting cylindromatosis (CYLD) [34]; or transfer circTEX2, which enhances cisplatin resistance by sponging miR-145 to upregulate ATP-binding cassette subfamily C member 1 (ABCC1) expression [83].Concurrently, exosomes from M2-TAMs also ferry various long non-coding RNAs (lncRNAs): lncRNA CRNDE augments cisplatin resistance by promoting NEDD4-1-mediated PTEN ubiquitination [84], whereas lncRNA MALAT1 fosters resistance in a glycolysis-dependent manner by activating the β-catenin signaling pathway to upregulate HIF-1α [30]. Circular RNAs such as circRNA_102191 promote epithelial-mesenchymal transition (EMT) and exacerbate resistance by regulating the miR-493-3p/XPR1 axis [85], and circGLIS3 can induce M2-TAM polarization via exosomal transfer, forming a vicious cycle [65]. Research demonstrates that exosomal MALAT1 from M2 macrophages cooperatively enhances aerobic glycolysis in gastric cancer cells by modulating β-catenin and HIF-1α signaling pathways, thereby promoting chemotherapy resistance [30]. Third, metabolic reprogramming instigated by conditions like hypoxia is deeply interwoven with the aforementioned mechanisms, jointly sculpting the resistant microenvironment. In hypoxic tumor microenvironments, upregulation of hypoxia-inducible factor-1α (HIF-1α) stimulates M2 macrophage generation. These cells, via VEGF secretion, activate the PI3K/Akt/Nrf2 pathway, consequently promoting tumor progression and chemotherapy resistance [86]. In gastric cancer, activated HIF1α signaling can drive high mobility group box 1 (HMGB1) expression, which recruits and polarizes M2 macrophages. These macrophages then exacerbate tumor cell fatty acid β-oxidation by producing growth differentiation factor 15 (GDF15), thereby promoting 5-FU resistance [57]. Furthermore, M2 macrophages can influence resistance through metabolite exchange. For example, in colorectal cancer, chemotherapy-induced interactions elevate CXCL7 expression in TAMs. This upregulated CXCL7 activates the CXCR2 receptor on tumor cells, leading to STAT1-dependent upregulation of phosphoglycerate dehydrogenase (PHGDH). This cascade promotes serine metabolism and S-adenosylmethionine (SAM) paracrine signaling, ultimately driving chemotherapy resistance [76].

In summary, M2-TAMs construct a potent, self-sustaining pro-resistance network through four interrelated mechanisms: activating core pro-survival pathways, employing exosomes to deliver various ncRNAs, secreting a complex cytokine network, and driving metabolic reprogramming in both themselves and tumor cells. A profound understanding of this intricate network not only unveils the key molecular underpinnings of gastric cancer chemoresistance but also establishes a solid groundwork for developing combination therapeutic strategies that target M2-TAMs and their mediated pathways (Fig. 3).

Fig. 3.

Multidimensional mechanisms of M2-TAMs in driving gastric cancer progression

This schematic delineates the central mechanisms by which M2-polarized tumor-associated macrophages (M2-TAMs) promote gastric cancer progression within the tumor microenvironment. The dynamic crosstalk between gastric cancer cells and surrounding M2-TAMs forms the core pro-tumorigenic unit. M2-TAMs drive tumor cell proliferation and chemoresistance by secreting factors like CXCL5 to activate key survival pathways such as PI3K/Akt/mTOR and JAK/STAT3 in cancer cells, and by delivering exosomes carrying molecules like MALAT1. Concurrently, they foster an immunosuppressive niche to facilitate immune escape by expressing PD-L1 to inhibit CD8⁺ T cell function and secreting inhibitory cytokines like IL-10 and TGF-β. Metabolically, lactate produced by glycolytic cancer cells promotes M2 polarization via the MCT-HIF-1α axis, while polarized M2-TAMs, in turn, reinforce tumor glycolysis through exosomal feedback, establishing a self-sustaining “lactate cycle” positive feedback loop. Furthermore, M2-TAMs induce tumor angiogenesis via robust secretion of pro-angiogenic factors like VEGF. During metastasis, they collaborate with stromal cells such as cancer-associated fibroblasts through specific signaling axes like C3-C3aR1 to construct a unique pre-metastatic niche, driving distant colonization and contributing to therapy resistance. This integrated network illustrates how M2-TAMs employ multidimensional and interconnected mechanisms to collectively promote gastric cancer proliferation, immune evasion, metabolic adaptation, angiogenesis, and metastasis, ultimately leading to disease progression and therapeutic failure.

Targeting M2-polarized tumor-associated macrophages: therapeutic strategies and prospects

Given the critical tumor-promoting role of M2-polarized tumor-associated macrophages (M2-TAMs) in gastric cancer, current research has explored therapeutic strategies from multiple perspectives. These strategies primarily focus on clearing or weakening the tumor-promoting functions of TAMs, inhibiting their recruitment to tumor sites, blocking their immunosuppressive functions, and repolarizing them into the anti-tumor M1 phenotype.

Clearing or weakening the tumor-promoting function of TAMs

A direct strategy involves clearing TAMs from the tumor microenvironment to weaken their pro-tumor effects. Studies show that targeting and clearing M2-TAMs can effectively inhibit tumor growth. For example, Ganodermanontriol (GAN) can inhibit M2 polarization of macrophages in the gastric cancer microenvironment, and its mechanism involves regulating STAT6 phosphorylation; in vivo, GAN treatment can inhibit tumor growth and reduce CD206-positive cell infiltration in tissues [87]. Furthermore, targeting glutathione peroxidase 4 (GPX4) has been confirmed to inhibit M2 macrophage polarization and enhance CD8 + T cell infiltration, thereby inhibiting tumor growth [88]. Regorafenib can modulate anti-tumor immunity by reversing the polarization of M2-TAMs, an effect independent of its anti-angiogenic function [89]. The specific antibody DKN-01, targeting secreted DKK1, can block M2-TAM polarization by activating the cGAS-STING pathway, thereby inhibiting gastric cancer tumor growth [90]. These studies provide experimental evidence for treating gastric cancer by clearing or inhibiting M2-TAMs.

Inhibiting the recruitment of M2-TAMs

Another important direction is blocking the migration and infiltration of monocytes into tumor sites by inhibiting chemokine axes such as CCL2/CCR2. Research finds that gastric cancer cells recruit and induce macrophages to polarize towards the M2 phenotype by secreting specific factors. For instance, the Inhibin beta A subunit (INHBA) secreted by gastric cancer cells can upregulate CCL2 expression and secretion, thereby promoting macrophage recruitment and M2 polarization [75]. Additionally, the expression of the Collagen type V alpha 2 chain (COL5A2) is associated with poor prognosis and M2 macrophage infiltration in gastric cancer, potentially contributing to disease progression by promoting M2 polarization [91]. Therefore, targeting the CCL2/CCL2-CCR2 axis or other chemokine pathways may be an effective means to prevent monocyte recruitment and M2-TAMs formation.

Promoting repolarization or reprogramming of M2-TAMs to the M1 phenotype

Repolarization or reprogramming of TAMs, aiming to convert tumor-promoting M2-type TAMs into anti-tumor M1-type, is a highly promising therapeutic strategy. Multiple studies confirm that macrophage phenotype conversion can be achieved by intervening in specific signaling pathways. For example, Dextran Sulfate (DS) can repolarize macrophages away from the M2 phenotype by inhibiting the IL-6/STAT3 signaling pathway, which in turn leads to inhibited angiogenesis, invasion, and migration of gastric cancer cells [92]. Another study found that Pentraxin-3 (PTX3) inhibits M2 macrophage polarization by inhibiting the phosphorylation of c-Jun N-terminal kinase 1/2 (JNK1/2), thereby suppressing the expression of IL-4 and IL-10 [43]. Moreover, traditional Chinese medicine formulas also show potential in regulating macrophage polarization. For instance, Modified Jianpi Yangzheng Decoction (mJPYZ) can reduce the content of pyruvate kinase M2 (PKM2) in exosomes derived from gastric cancer cells, thereby alleviating exosomal PKM2-induced M2-TAMs differentiation [26]. Wang’s team confirmed that the endogenous opioid pentapeptide MENK can induce the conversion of gastric cancer TAMs from M2 to M1 [93]. In traditional Chinese medicine, modified Jianpi Yangzheng Decoction can reprogram TAMs from M2 to M1 through a PI3Kγ-dependent mechanism [94], Huangqi Guizhi Wuwu Decoction can upregulate α7nAchR expression to modulate M1/M2 balance [95], and Qingrexiaoji Recipe can regulate M2 macrophage polarization by modulating the miR-29a-3p/HDAC4 axis [96]. The PR-Gel hydrogel platform developed by Yang’s team also exerts anti-gastric cancer effects through TAMs reprogramming [97]. Collectively, these studies demonstrate that pharmacological or natural compound intervention in key signaling pathways can effectively drive the repolarization of TAMs from a tumor-promoting (M2) to a tumor-suppressive (M1) phenotype.

Functional blockade of M2-TAMs

Interfering with key pathways through which M2-TAMs exert immunosuppressive or tumor-promoting functions is an embodiment of precision therapy. For example, targeting immune checkpoints or signaling molecules can reverse T cell function inhibition mediated by TAMs. Research shows that exosomes derived from gastric cancer cells can promote macrophage M2 polarization by delivering circSMARCC1, which upregulates U2AF2 expression [98]. Blocking this exosome-mediated communication may impair M2-TAM function. Furthermore, the anti-DKK1 antibody DKN-01 can block macrophage M2 polarization by activating the cGAS/STING pathway, thereby inhibiting gastric cancer progression [90]. Another example is that Sialic acid-binding Ig-like lectin 11 (SIGLEC11) secreted by gastric cancer cells promotes macrophage M2 polarization via the AKT-mTOR signaling pathway [99]. Therefore, developing inhibitors targeting these key signaling pathways (such as those mediated by STAT6, cGAS/STING, or AKT-mTOR) or specific molecular targets (such as DKK1 and SIGLEC11) holds promise for directly blocking the immunosuppressive and tumor-promoting functions of M2-TAMs.

Synergistic therapy targeting M2-TAMs combined with immune checkpoint inhibitors

Given that M2-TAMs are a key contributor to resistance against immune checkpoint inhibitors (ICIs) such as anti-PD-1, integrating strategies that target M2-TAMs with ICI therapy has emerged as a core approach to circumvent resistance and enhance therapeutic efficacy. This synergy aims to achieve more comprehensive remodeling of the tumor microenvironment [100]. For example, when Foretinib is combined with anti-PD-1 drugs, it can reduce the proportion of TAMs and inhibit M2-TAMs polarization, thereby enhancing anti-tumor effects in vivo [101]. The gastrin-CCK-BR pathway, discovered by Cao et al. in gastric cancer models, when combined with anti-PD-1 drugs, can significantly reduce M2-TAM polarization and increase the number of CD8 + T cells [102]. Methionine Restriction (MR) can also synergize with PD-1 blockade to promote M1 polarization and inhibit M2 polarization in vitro [103]. Additionally, Palmitic acid combined with γ-interferon can promote M1-TAMs expansion and inhibit M2-TAMs proliferation via the TLR4 signaling pathway, thereby inhibiting gastric cancer progression [104]. M2-TAMs-targeting drugs for gastric cancer treatment are continually being developed, and the field has already seen the emergence of nanomedicines specifically targeting M2-TAMs. These advances collectively paint a promising outlook for the future of gastric cancer treatment (Table 1).

Table 1.

Summary of drugs associated with targeting M2-TAMs

Therapeutic paradigm	Mechanism/target	Representative strategy/drug	Development stage (for GC)	Key pathway/function	References/notes
I. Clearance, Inhibition of Recruitment, and Weakening Function	Block monocyte recruitment	Targeting CCL2/CCR2 axis	Preclinical/Early Clinical	CCL2-CCR2 chemokine signaling	[75]
	Inhibit M2 polarization/Clear TAMs	Regorafenib	Phase III (Completed, combination)	p38 kinase/Creb1/Klf4 axis	[89] NCT01298586
	Inhibit M2 polarization	Ganodermanontriol (GAN)	Preclinical Research	Inhibits STAT6 phosphorylation (JAK-STAT pathway)	[87]
	Inhibit M2 polarization	Pentraxin-3 (PTX3)	Preclinical Research	Inhibits JNK1/2 phosphorylation, downregulates IL-4/IL-10	[43]
	Inhibit M2 polarization	Dextran Sulfate	Preclinical Research	Inhibits IL-6/STAT3 pathway	[92]
	Inhibit M2 polarization	Targeting Collagen type V alpha 2 chain (COL5A2)	Preclinical Research	Associated with M2 infiltration, mechanism to be further elucidated	[91]
II. Functional Blockade and Targeted Inhibition	Block M2 polarization signaling	DKN-01 (anti-DKK1 mAb)	Phase I (Completed)	Activates cGAS-STING pathway	[90] NCT02013154
	Block M2 polarization signaling	Targeting SIGLEC11	Preclinical Research	AKT-mTOR signaling pathway	[99]
	Block exosome-mediated M2 induction	Intervening exosomal RNAs like circSMARCC1	Preclinical Research	Blocks “education” of macrophages by tumor cells	[98]
III. Reprogramming (Repolarization)	Promote M1 polarization/Phenotype switch	Sophoridine	Preclinical Research	TLR4/IRF3 signaling pathway	[41]
	Promote M1 polarization/Phenotype switch	Methionine Enkephalin (MENK)	Preclinical Research	OGFr/PI3K/AKT/mTOR pathway	[93]
	Promote M1 polarization/Phenotype switch	Circular RNA circSOD2	Preclinical Research	Targets miR-1296/STAT1 axis	[105]
	Promote M1 polarization/Phenotype switch	R848 (Resiquimod)/CMA-R848 nanomicelles	Preclinical (Nanomicelles)	TLR7/8-MyD88 signaling pathway	[103]
	TCM formula reprogramming	Modified Jianpi Yangzheng Decoction (mJPYZ)	Preclinical Research	PI3Kγ/NF-κB pathway	[94]
	TCM formula reprogramming	Huangqi Guizhi Wuwu Decoction	Preclinical Research	Modulates α7nAchR, affecting TGF-β/NF-κB/JAK-STAT	[95]
	TCM formula reprogramming	Qingrexiaoji Recipe	Preclinical Research	Regulates miR-29a-3p/HDAC4 axis	[96]
	Novel delivery system-driven reprogramming	PR-Gel hydrogel (loaded with multiple drugs)	Preclinical Research	Local sustained release, induces TAM repolarization	[97]
IV. Synergistic and Combination Therapy	Targeting TAM + Immune Checkpoint Inhibitor (ICI)	Regorafenib + anti-PD-1	Under clinical trial	Reverses M2 polarization + relieves T cell inhibition	[58, 89, 101]
	Targeting TAM + ICI	Targeting Gastrin-CCK-BR pathway + anti-PD-1	Preclinical/Early Clinical (Vaccine)	Reduces M2-TAMs, increases CD8 + T cells	[102] NCT02233712
	Targeting TAM + ICI	Foretinib + anti-PD-1	Preclinical Research	Reduces TAMs, inhibits M2 polarization, synergizes with ICI	[101]
	Metabolic intervention + Immunotherapy	Dietary Methionine Restriction (MR) + anti-PD-1	Phase I/Preclinical	Global metabolic reprogramming promoting M1 polarization	[103, 106] NCT03574194
	Metabolic intervention + Immunotherapy	Palmitic acid + γ-interferon	Preclinical Research	Modulates M1/M2 balance via TLR4 pathway	[104]
	Chemo-immuno-reprogramming synergy	CMA-R848 nanomicelles (co-delivery)	Preclinical Research	Chemotherapy killing + TLR agonist reprogramming TAMs	[103]
V. Targeting Metabolism and Niche (Emerging Directions)	Intervene metabolic product signaling	Targeting lactate-MCT-HIF1α axis	Preclinical Research	Lactate-mediated M2 polarization & immunosuppression	[64]
	Intervene metabolic pathways	GPX4 knockdown/targeting kynurenine metabolism	Preclinical Research	Modulates redox & kynurenine metabolism, inhibits M2 polarization	[88]
	Disrupt metastatic niche	Targeting C3a-C3AR1 or SPP1 + TAMs	Preclinical/Proof-of-concept	Disrupts immunosuppressive module of TAMs & CAFs	[107]

Challenges and future directions in M2-polarized tumor-associated macrophage research

Major challenges in research: TAM heterogeneity and off-tumor effects

The inherent heterogeneity of tumor-associated macrophages (TAMs) constitutes a fundamental challenge in this field. While historically simplified into a binary framework of anti-tumor M1 versus pro-tumor M2 phenotypes, advanced profiling techniques—particularly single-cell RNA sequencing—reveal that TAMs exist as a spectrum of complex cellular states within the tumor microenvironment (TME), far exceeding the M1/M2 paradigm [108]. In gastric cancer, this heterogeneity is markedly evident. For example, an integrated single-cell and bulk RNA sequencing analysis utilizing the machine learning framework EcoTyper successfully categorized gastric cancer TAMs into distinct cellular states and ecotypes, identifying specific M2-state markers that correlate with patient prognosis [109]. These markers allow for the stratification of patients into subgroups characterized by divergent survival outcomes and varying degrees of M2 macrophage infiltration. Corroborating this complexity, a study in glioblastoma highlighted significant intratumoral heterogeneity in TAM surface markers (e.g., CD204, CD163), emphasizing that a nuanced understanding of TME architecture is critical for developing effective, personalized treatment strategies [110]. This diversity stems from multiple factors, including differences in cellular origin (monocyte-derived vs. tissue-resident), spatial positioning within the TME, and exposure to dynamic local signaling cues [111, 112]. Consequently, research or therapeutic interventions that treat TAMs as a homogeneous population risk misrepresenting their functional roles in gastric cancer pathogenesis and may lead to inaccurate predictions of therapeutic response.

The clinical translation of M2-TAM-targeting strategies is further complicated by the imperative to minimize off-tumor effects. Given the indispensable role of macrophages in systemic homeostasis, immune surveillance, and tissue repair, broad depletion or inhibition risks severe adverse outcomes, such as increased susceptibility to infection or impaired wound healing [113]. This has spurred a shift toward therapeutic paradigms focused on the specific reprogramming of pro-tumor TAMs rather than their non-selective elimination. For instance, photodynamic therapy-generated reactive oxygen species have been explored as a means to convert M2-TAMs into tumoricidal M1 phenotypes [114]. A central hurdle, however, lies in achieving precise spatial targeting—ensuring interventions act selectively on TAMs within the tumor while sparing functionally essential macrophages in healthy tissues like the liver and spleen [115]. Innovations in drug delivery, such as nanotechnology-based carriers, cell-membrane engineered vesicles, or “smart” materials responsive to TME-specific conditions (e.g., acidic pH, overexpressed enzymes), represent promising avenues to enhance specificity and mitigate systemic toxicity.

A significant translational bottleneck arises from the limitations of current experimental models. While in vitro co-culture systems are invaluable for delineating basic mechanisms of gastric cancer cell-macrophage crosstalk—such as the induction of M2 polarization via tumor-derived extracellular vesicles (EVs) or lactate [71]—they cannot recapitulate the intricate three-dimensional architecture, multicellular complexity, hemodynamic forces, and metabolic gradients of the in vivoTME. To bridge this gap, researchers are pioneering more sophisticated models. One example is a microfluidic chip integrating a three-dimensional co-culture of osteosarcoma cells, human TAMs, and endothelial cells, designed to simulate intratumoral mechanical stress, thereby offering a more physiologically relevant platform for evaluating TAM-targeting therapies [116]. Advancing gastric cancer research similarly demands the development of complex ex vivo and in vivo models that faithfully mirror tumor heterogeneity, stromal composition, and immune cell spatial relationships to reliably assess therapeutic efficacy and safety.

Finally, a comprehensive understanding of the dynamic, bidirectional crosstalk between gastric cancer cells and TAMs remains elusive, impeding the rational design of targeted therapies. This interaction is multifaceted: gastric cancer cells actively shape the TME by secreting factors (e.g., CCL2, exosomes) that recruit and polarize monocytes toward an M2 phenotype [20, 117]. In turn, M2-TAMs reciprocally fuel tumor progression by secreting growth factors, cytokines, exosomes, and metabolites that promote cancer cell proliferation, invasion, metastasis, chemotherapy resistance, and immune evasion [118]. Moreover, TAMs engage in extensive cross-communication with other stromal and immune cells, collectively fortifying an immunosuppressive niche. Single-cell analyses in colorectal cancer, for instance, have identified functionally discrete TAM subsets (e.g., CCL20+, APOE+, SLC40A1+) linked to differential treatment responses [109]. Although parallel investigations in gastric cancer are emerging, a deeper dissection of the molecular drivers, spatiotemporal dynamics, and evolutionary trajectory of these cellular interactions—leveraging multi-omics, spatial transcriptomics, and intravital imaging—is essential. Only by decoding this complex interactional network can we identify the most vulnerable, druggable nodes for effective combination therapies.

Innovations in therapeutic strategies targeting M2 polarization

Innovative therapeutic strategies targeting M2-polarized TAMs are pivotal for dismantling the immunosuppressive TME and overcoming therapy resistance in gastric cancer. These approaches converge on three fronts: developing specific pathway inhibitors, harnessing exosomes for targeted intervention, and synergizing metabolic modulation with immunotherapy, all aimed at precision remodeling of the tumor immune landscape.

The development of specific M2 polarization inhibitors represents a direct strategy to subvert TAMs’ pro-tumor functions. Evidence suggests that pharmacologically disrupting key nodes in M2-polarizing signaling cascades can effectively reprogram their phenotype. In gastric cancer, the traditional Chinese medicine component Ganodermanontriol (GAN) inhibits M2 polarization by attenuating STAT6 phosphorylation [87]. Similarly, in hepatocellular carcinoma, targeting serine/arginine-rich splicing factor 10 (SRSF10) suppresses M2 macrophage polarization and potentiates anti-PD-1 therapy [119]. These findings underscore the therapeutic promise of small-molecule inhibitors or gene-silencing tools (e.g., shRNA, antisense oligonucleotides) directed against master regulators like STAT6 or SRSF10. Illustratively, decoy oligodeoxynucleotides (ODNs) that sequester STAT6 can inhibit M2-like polarization and blunt immune escape in pancreatic cancer [120]. Gene therapy targeting macrophage surface receptors, such as using a viral-free vector to deliver short hairpin RNA against Mincle (uSMB-shMincle), also effectively modulates TAM polarization and curbs tumor progression [121]. These modalities offer precise molecular tools for the direct “reeducation” of TAMs.

Exosome-based interventions constitute a second, highly promising frontier. Leveraging exosomes as natural biocompatible delivery vehicles capitalizes on their immune-evasive properties and inherent targeting capabilities. Exosomes derived from M2 macrophages (M2-Exo) are particularly attractive as drug carriers [122]. Proof-of-concept studies have successfully loaded M2-Exo with anti-inflammatory cytokine (IL-10) plasmid DNA and chemotherapeutic agents for rheumatoid arthritis treatment, achieving synergistic anti-inflammatory effects via macrophage repolarization [112]. In gastric cancer, where M2-TAM exosomes transfer oncogenic long non-coding RNAs (e.g., MALAT1) to promote glycolysis and chemoresistance [30], intercepting this communication—either by inhibiting exosome biogenesis/secretion or by engineering exosomes to deliver silencing RNA (siRNA)—offers a novel strategy to disrupt TAM-mediated support. Furthermore, hybrid exosome technologies, such as fusing M2 macrophage exosomes with those from bone marrow mesenchymal stem cells, can enhance tropism to disease sites (e.g., bone metastases) and synergistically modulate macrophage polarization, providing a blueprint for next-generation targeted therapeutics [122].

The integration of metabolic modulation with immunotherapy forms a potent combinatorial strategy to counteract resistance. Metabolic reprogramming, especially lactate accumulation, is a linchpin connecting M2 polarization to immunotherapy failure. In hepatocellular carcinoma, SRSF10 fuels lactate production via the MYB/glycolysis axis; lactate, in turn, induces histone lactylation to reinforce M2 polarization, which suppresses CD8 + T cells and drives anti-PD-1 resistance [119]. Co-targeting this metabolic axis (e.g., with SRSF10 inhibitors) alongside PD-1 blockade can thus resensitize tumors. Analogously, in EBV-associated gastric cancer, M2 macrophages secrete copious matrix metalloproteinase 9 (MMP9), inducing T cell exhaustion and resistance to TCR-T cell therapy. Combining MMP9 inhibition with TCR-T cells restores T cell function and enhances tumor killing [123]. Beyond lactate, targeting other metabolic pathways also holds promise. For example, nanocomposites that scavenge reactive oxygen species (ROS) can be used to polarize macrophages toward an M2-like phenotype for anti-inflammatory therapy, demonstrating the plasticity of metabolic-immune cross-talk [124]. These insights collectively advocate for therapeutic regimens that concurrently disrupt tumor/TAM-specific metabolic dependencies and rejuvenate anti-tumor immunity, presenting a robust approach to surmount treatment resistance in gastric cancer.

Future research priorities

A paramount future direction involves elucidating the context-dependent functions of M2-polarized macrophages across the molecularly diverse landscape of gastric cancer subtypes. Gastric cancer exhibits pronounced heterogeneity, with subtypes—such as the EBV-positive, microsatellite instability (MSI), genomically stable (GS), and chromosomal instability (CIN) classifications per The Cancer Genome Atlas (TCGA)—displaying distinct TME signatures and immune infiltration patterns [125]. M2 macrophage abundance is closely linked to specific subtypes; for instance, mesenchymal-like, high-risk subtypes are enriched with both M2 macrophages and cancer-associated fibroblasts, correlating with worse prognosis [125]. Intriguingly, while high CD47 expression in MSI subtypes associates with M1 macrophage infiltration, its prognostic benefit is attenuated, suggesting tumor-intrinsic factors may modulate M2 macrophage activity [126]. Another integrative transcriptomic and single-cell study delineated two TME-metabolism-based subtypes, with the high-risk group exhibiting elevated M2 infiltration and unique metabolic rewiring [125]. Moving forward, employing high-resolution technologies like single-cell and spatial transcriptomics to map the transcriptional identities, spatial organization, and cellular interaction networks of M2 macrophages within each subtype will be crucial. This will clarify subtype-specific pro-tumor mechanisms and lay the groundwork for tailored immunotherapeutic strategies.

A second critical priority is to decipher the multifaceted metabolic and signaling interplay between M2 macrophages, other immune cells, and tumor cells. M2 macrophages are embedded in a web of metabolic coupling and paracrine communication. Gastric cancer cell-derived lactate, exported via monocarboxylate transporters (MCTs), activates HIF1α in macrophages to drive M2 polarization [64]. Reciprocally, M2-TAM-derived exosomes, loaded with molecules like MALAT1, are internalized by tumor cells, stabilizing δ-catenin and HIF-1α to co-activate β-catenin and HIF-1α pathways, thereby amplifying aerobic glycolysis, proliferation, and chemoresistance [127]. Beyond tumor cells, M2 macrophages actively engage with other stromal players. Cancer-associated fibroblasts (CAFs), by secreting POSTN, activate Akt in macrophages to promote their chemotaxis, fostering an ICI-resistant niche [128]. Furthermore, M2 macrophages collaborate with regulatory T cells (Tregs) to suppress CD8 + T cell function [117], while their presence correlates with collagen expression (e.g., COL1A1), implicating them in extracellular matrix remodeling that indirectly shapes immune activity [118]. Future research must harness multi-omics, metabolic flux analysis, and advanced co-culture systems to untangle the precise exchange mechanisms of metabolites (lactate, lipids, amino acids) and exosomal cargo (circRNAs, miRNAs) within this network, revealing how co-metabolic dependencies are established to fuel tumor growth and immune evasion.

The ultimate translational objective is to develop safe, effective, and precise M2 polarization modulators. Current research has identified several target classes: (i) Direct effectors of polarization pathways (e.g., STAT6, PI3K-γ). Inhibitors like the PI3K-γ-selective IPI549 can reverse the immunosuppressive function of lipid-laden TAMs [127]. (ii) Upstream tumor-derived drivers (e.g., IRAK1, ASPN, INHBA, TMEM205) whose inhibition indirectly attenuates M2 recruitment and polarization [117, 129]. (iii) Intercellular communication vectors, notably exosomes and their non-coding RNA cargo. Targeting specific axes, such as the exosomal circATP8A1/miR-1-3p/STAT6 circuit [130] or SERPINE1-mediated let-7 g-5p delivery [131], could disrupt tumor cell “education” of macrophages. The path to clinical application, however, is fraught with challenges pertaining to target specificity, delivery efficiency, on-target/off-tumor toxicity, and preservation of systemic immune homeostasis. Future efforts must therefore leverage innovative platforms—such as nanotechnology for targeted delivery, antibody-drug conjugates (ADCs) for precise cytotoxicity, and engineered cellular therapies like chimeric antigen receptor macrophages (CAR-M) [132]—to transform these mechanistic insights into viable, next-generation immunotherapies for gastric cancer.

Summary

Gastric cancer is a molecularly complex and clinically aggressive malignancy. As this review synthesizes, M2-polarized tumor-associated macrophages (M2-TAMs) emerge as pivotal orchestrators within the gastric cancer microenvironment, exerting multifaceted influence across the continuum of tumor initiation, progression, immune evasion, and therapeutic resistance. Contemporary research solidly positions M2-TAMs as a central regulatory nexus in gastric cancer pathogenesis while concurrently illuminating the persistent challenges and emergent opportunities in both foundational biology and clinical translation. Their integration into tumor biology is governed by a confluence of dysregulated signaling pathways (e.g., STAT3, PI3K/Akt, NF-κB) and profound metabolic adaptations (e.g., skewed arginine metabolism, enhanced fatty acid oxidation). Through these mechanisms, M2-TAMs establish a profoundly immunosuppressive and pro-tumorigenic niche. They drive disease progression by secreting a battery of cytokines (e.g., IL-6, TGF-β, IL-10) that paralyze cytotoxic T cells and recruit regulatory T cells (Tregs); by releasing pro-angiogenic factors (e.g., VEGF, MMPs) to nourish tumor growth and facilitate metastasis; by activating proliferative and survival pathways in cancer cells directly or via exosomal miRNAs and lncRNAs; and by instigating metabolic reprogramming that confers resistance to chemotherapy and immunotherapy. Notably, M2-TAMs contribute to an acidic, lactate-rich TME that further reinforces immune exclusion.

This mechanistic understanding has catalyzed the exploration of M2-TAMs as a compelling therapeutic target. Strategic avenues include inhibiting their recruitment (e.g., blocking CCL2/CCR2), repolarizing them toward an anti-tumor phenotype (e.g., via CD40 or TLR agonists), functionally disabling their immunosuppressive output (e.g., using CSF-1R inhibitors), or hijacking their tumor-homing propensity for targeted drug delivery. Preclinical validation of these approaches is encouraging, with several candidates advancing into early-phase clinical trials. The paramount challenge now resides in intelligently integrating these TAM-focused strategies with established modalities—chemotherapy, radiotherapy, and immunotherapy—to overcome resistance, achieve synergistic efficacy, and manage potential immune-related toxicities. Future research must pivot towards embracing the spatial, temporal, and functional heterogeneity of TAMs, demanding more “discriminatory” therapeutic agents. Concurrently, translating these insights will require meticulously designed clinical trials, ideally biomarker-enriched, and vigilant monitoring of long-term patient outcomes and quality of life. By deepening our comprehension of and intervention against the M2-TAM hub within the gastric cancer microenvironment, we hold tangible promise for fundamentally reshaping the therapeutic paradigm and improving the outlook for patients confronting this formidable disease.

Author contributions

J.D., A.D., N.W., Y.C., and Y.Z. contributed to the writing of the manuscript. Y.Z., Y.C. and J. D. conceived the idea and contributed to funding acquisition. J.D., A.D. and N.W. prepared the original draft. Y.Z. and Y.C. reviewed and edited the manuscript.S.W. helps with editing articles and creating schematic diagrams.

Data availability

No datasets were generated or analysed during the current study.

Declarations

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This review article does not involve any primary data collection from human participants or animal experiments. As such, it does not require ethical approval from a committee. The study solely relies on the analysis and synthesis of existing published literature, ensuring compliance with ethical standards in academic research. Since this is a review article and does not involve direct participation of individuals, consent to participate is not applicable. The research is based on the examination of previously published studies and data, which have already undergone ethical scrutiny by their respective authors and institutions.

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This review article does not contain any original data or personal information that would require consent for publication. All information included in the manuscript is derived from publicly available sources and has been appropriately cited. Therefore, consent to publish is not necessary for this study.

Competing interests

The authors declare no competing interests.