Tumor-associated macrophages (TAMs) are macrophages that either infiltrate tumor tissues or reside in the tumor microenvironment (TME). These specialized immune cells play crucial roles in tumor growth, angiogenesis, immune modulation, metastasis, and chemoresistance. TAMs include different subpopulations, primarily categorized as M1 and M2 types based on their polarization and activity. M1 macrophages exhibit a pro-inflammatory phenotype with anti-tumor effects, while M2 macrophages have an anti-inflammatory phenotype and contribute to tumor progression. These highly versatile cells respond to stimuli from tumor cells and other TME components, such as growth factors, cytokines, chemokines, and enzymes, leading to complex interactions and influencing both pro-tumor and anti-tumor processes.

Cellular Origin and Polarization of TAMs

TAMs originate from bone marrow-derived circulating monocytes, which differentiate into M0 macrophages and then polarize into M1 or M2 phenotypes in response to environmental signals. Notably, macrophages can also originate from embryonic precursors, bypassing the monocytic intermediate. Interactions between macrophages and tumor cells begin at the M0 stage, influencing subsequent polarization and recruitment of additional macrophages to the tumor site via chemokines released by cancer stem cells (CSCs) and tumor cells. M1 polarization is primarily induced by factors such as IFN-γ, LPS, and GM-CSF, leading to the secretion of pro-inflammatory cytokines like IL-6, IL-12, IL-23, and TNF-α, which enhance inflammatory responses and cytotoxic effects against pathogens and tumor cells. In contrast, M2 polarization includes several subtypes (M2a, M2b, M2c, M2d), each influenced by specific stimuli such as CSF-1, IL-4, IL-13, and IL-10, related to parasitic infections, tissue remodeling, allergic diseases, and angiogenesis. Under TME conditions of hypoxia, high lactate levels, inflammation, and oxidative stress, macrophages tend to exhibit an M2 phenotype characterized by elevated levels of IL-10, TGF-β, pro-angiogenic factors, and tissue remodeling enzymes, thus promoting angiogenesis, immune suppression, and tumor progression.

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Crosstalk Between TAMs and Tumor Cells

TAMs secrete chemokines and cytokines such as IL-6, IL-8, and IL-10 that actively promote cancer progression. Notably, IL-8 released by TAMs has cytotoxic effects on T lymphocytes. Various mechanisms of crosstalk between tumor cells and TAMs play a key role in inducing immune suppression. The PD-1/L1 signaling pathway exacerbates tumor immune evasion by impeding the normal functions of macrophages and other immune effector cells. Additionally, interactions between B7-H3 and its receptor are associated with the inhibition of T lymphocytes, further promoting tumor immune escape. The "don't eat me" signals like CD47 and CD24/siglec-10 overexpressed by tumor cells are recognized as normal self-cells by macrophages, thus avoiding phagocytosis. Another important mechanism of tumor escape involves the LILRB1/MHC class I component β2-microglobulin, which inhibits macrophage phagocytosis of tumor cells.

Figure 1. Tumor-associated macrophages and tumor cells: mechanisms of interaction and immune evasion. (Toledo B, et al., 2024)

Role of Extracellular Vesicles in the Tumor Microenvironment

Extracellular vesicles facilitate intercellular communication by transporting various molecules, including mRNA, circRNA, lncRNA, miRNA, lipids, and proteins. Notably, extracellular vesicles exhibit dynamic changes during the transport process from source cells to target cells. ApoE, highly expressed in TAMs, transfers to cancer cells through extracellular vesicles and activates the PI3K-Akt signaling pathway, promoting cytoskeletal remodeling, epithelial-mesenchymal transition (EMT), and cancer cell migration. Other crosstalk mechanisms, such as Eph44-ephrin interactions, regulate immune cell processes, including proliferation, survival, apoptosis, activation, and migration. CD44, a transmembrane adhesion molecule, plays a crucial role in the binding and metabolism of hyaluronic acid (HA) and acts as an effective phagocytic receptor, influencing inflammation, phagocytosis, and multidrug resistance. Interactions like CD44-HA, BTN3N3-L-SECtin, CD90-CD11b, and Eph44-ephrin also trigger signals that support cancer stem cell maintenance.

Activation Pathways of TAMs

M1 macrophages express innate immune receptors such as toll-like receptors (TLRs) during development and maturation, enabling them to recognize pathogen-associated molecular patterns like microbial LPS. Activation of downstream signaling pathways occurs through ligand binding of LPS to TLR4, including MYD88-dependent pathways or IFN5-dependent pathways, which further signal through NF-κB or p38-MAPK pathways, respectively. These pathways collectively promote the expression of inflammatory factors and M1 macrophage polarization. Additionally, IFN-γ binding to its receptor induces M1 polarization by activating JAK/STAT1 and PI3K/AKT/Fos/Jun pathways. The latter pathways are also activated upon receptor tyrosine kinase ligation, such as MER. Inhibitors like SOCS1/3 can suppress TLR4/MyD88/NF-κB and JAK/STAT1 pathways, thereby inhibiting M1 polarization activity by blocking upstream signal transmission.

In contrast, M2 polarization primarily occurs through interactions between IL-4/6 and their receptors, activating JAK/STAT3/6 signaling pathways. Furthermore, activation of TGF-βR through PI3K/Akt/mTOR and TGF-βR/Smad/party pathways leads to downstream signal transmission. Tumor-derived Wnt ligands also stimulate M2 polarization via the Wnt/β-catenin signaling pathway. Notch signaling promotes M2 polarization through a positive feedback loop, enhancing the production of IL-6, IL-10, and IL-12. SOCS3 inhibition prevents M2 polarization by blocking these pathways. Certain extracellular vesicle miRNAs regulate macrophage polarization by affecting the aforementioned signaling pathways or transcription factors. Additionally, oxidative stress detection leads to upregulation of HIF-1α and HIF-2α, where HIF-1α favors M1 polarization and HIF-2α promotes M2 polarization.

Figure 2. Key pathways in tumor-associated macrophage (TAM) activation and polarization. (Toledo B, et al., 2024)

Anti-Tumor and Pro-Tumor Processes of TAMs

A key feature of macrophages is their inherent plasticity, with two extremes identified as M1 and M2 polarization. Depending on the paracrine signals received, tissue type, microenvironment, and tumor stage, macrophages may adopt one phenotype or the other. Anti-tumor M1-like macrophages contribute to T cell recruitment and immune activation, particularly by stimulating NK cells. They exhibit direct cytotoxicity and phagocytic activity against tumor cells. Additionally, M1-like macrophages assist in tissue repair, promote the maturation of antigen-presenting cells (APCs) essential for effective antigen presentation, and actively induce cancer cell apoptosis. Pro-tumor M2-like macrophages, under hypoxic TME conditions, release immune-suppressive mediators that support tumor proliferation, angiogenesis, invasion, and metastasis. They induce epithelial-mesenchymal transition, promote tissue remodeling and inflammation, and increase the self-renewal rate of CSCs.

Research Directions Related to TAMs

Recent research on TAMs highlights the need for strategies to reprogram TAMs by eliminating their pro-tumor functions and enhancing their anti-tumor potential. Developing strategies to disrupt communication between tumor cells and the TME remains a significant area of research. Understanding the regulatory mechanisms of TAM phenotypes and functions using emerging technologies and bioinformatics analysis may lead to new therapeutic targets and strategies. Key research directions include:

1. Developing new molecular targets to interfere with TAM-tumor cell interactions through drug or gene therapy.

2. Utilizing nanotechnology and delivery systems to precisely target TAMs for targeted therapy.

3. Exploring the potential of TAMs in immunotherapy, such as reprogramming TAMs through immune checkpoint inhibitors or CAR-T cell therapies to enhance anti-tumor effects.

4. Investigating TAM heterogeneity across different tumor types and subtypes to reveal specific regulatory mechanisms in various tumor contexts.

Figure 3. Macrophage diversity in tumor progression and therapy resistance: functional polarization and impacts. (Cassetta L, et al., 2018)