Exploring the Multifunctional Role of Lung Macrophages in Cancer Metastasis

Kerber Hsieh^*
*Correspondence: Kerber Hsieh, Department of Pulmonology, National Hospital for Neurology and Neurosurgery, London WC1N 3BG, UK, Email:

Introduction

Cancer metastasis is a complex, multistep process through which cancer cells spread from their primary site to distant organs, often leading to poorer prognoses and reduced survival rates. Metastatic disease is responsible for approximately 90% of cancer-related deaths and its ability to evade the immune system, interact with the tumor microenvironment and promote tissue remodeling complicates therapeutic interventions. Among the various immune cells that influence the metastatic process, lung macrophages have garnered significant interest due to their essential involvement in shaping the tumor microenvironment and modulating cancer progression. These macrophages, a crucial component of the innate immune system, are located within the lungs, which often serve as a primary site for metastatic dissemination in cancers, such as breast, colorectal and melanoma. Lung macrophages, particularly Tumor-Associated Macrophages (TAMs), play a multifunctional role in cancer metastasis. Their roles are diverse, encompassing immune surveillance, tissue remodeling and immune modulation, which directly and indirectly affect the capacity of cancer cells to spread and colonize the lungs. In this article, we will explore the multifaceted contributions of lung macrophages in cancer metastasis, focusing on their interactions with tumor cells, their impact on immune responses and their potential as therapeutic targets in cancer treatment [1].

Description

Macrophages are specialized immune cells that exist in nearly every tissue in the body, including the lungs. These cells are derived from monocytes that migrate into tissues and differentiate into macrophages in response to local cues. Macrophages are classified into two main phenotypes: the classically activated M1 macrophages and the alternatively activated M2 macrophages. M1 macrophages are typically associated with pro-inflammatory responses and anti-tumor immunity, whereas M2 macrophages have an immunosuppressive role and are linked to tumor progression, tissue remodeling and metastasis. In the context of cancer, macrophages in the Tumor Microenvironment (TME) are primarily polarized towards the M2 phenotype. These M2 macrophages, often referred to as Tumor-Associated Macrophages (TAMs), contribute to the progression of cancer by promoting angiogenesis, facilitating immune evasion and supporting tissue remodeling that allows metastatic cells to thrive and spread. TAMs also secrete cytokines, growth factors and enzymes that modify the Extracellular Matrix (ECM) and create a permissive environment for tumor cell migration and invasion [2]. Macrophages can accumulate in tumors through several mechanisms. One of the key drivers is the secretion of chemokines and growth factors by tumor cells, which attract monocytes to the site of the tumor. Once in the tumor microenvironment, these monocytes differentiate into macrophages and the interaction between TAMs and cancer cells further enhances tumor progression. In the lungs, a highly vascularized tissue, this process is particularly relevant for the metastasis of cancer cells that have initially disseminated from distant sites. The lungs are a common site for the metastasis of a variety of solid tumors, as their rich blood supply provides an accessible route for Circulating Tumor Cells (CTCs) to colonize. Lung macrophages are among the first immune cells to encounter these CTCs and their response can significantly influence whether or not the tumor cells successfully establish metastatic growth. The interactions between lung macrophages and tumor cells can either support or inhibit metastasis, depending on the polarization of the macrophages and the signaling pathways that are activated. In a healthy immune system, macrophages play a key role in the surveillance and clearance of abnormal cells, including tumor cells. Macrophages can recognize and engulf tumor cells through a process called phagocytosis, facilitated by the expression of Pattern Recognition Receptors (PRRs) on their surface, which detect Damage-Associated Molecular Patterns (DAMPs) and Pathogen-Associated Molecular Patterns (PAMPs). In the lungs, this immune surveillance function is critical for preventing the early stages of metastasis [3]. The Extracellular Matrix (ECM) plays a crucial role in maintaining tissue architecture and regulating cell behavior. During cancer metastasis, the ECM undergoes significant remodeling to enable the migration and invasion of tumor cells. Lung macrophages, particularly TAMs, are actively involved in this process through the secretion of enzymes such as Matrix Metalloproteinases (MMPs), which degrade the ECM and facilitate the invasion of cancer cells into the surrounding tissues. The remodeling of the ECM also creates a more favorable environment for tumor growth by enhancing angiogenesis and increasing the availability of nutrients and oxygen. In addition, the altered ECM composition can influence the ability of tumor cells to interact with other cells within the metastatic niche, including stromal cells and endothelial cells, further promoting metastasis. One of the key challenges in cancer treatment is the ability of tumors to evade immune surveillance. Lung macrophages, particularly TAMs, contribute to this immune evasion by creating an immunosuppressive environment in the tumor microenvironment. As mentioned previously, TAMs secrete a variety of cytokines that suppress the immune response. TGF-β and IL-10 are two of the most prominent immunosuppressive cytokines secreted by TAMs. These cytokines inhibit the activity of cytotoxic T cells and NK cells, which are crucial for killing cancer cells. Additionally, they can promote the expansion of regulatory T cells (Tregs), which further dampen anti-tumor immunity [4,5].

Conclusion

Lung macrophages play a multifaceted and dynamic role in cancer metastasis. As key components of the innate immune system, they both promote and suppress tumor progression, depending on their polarization and the signals they receive from the tumor microenvironment. While they are essential for immune surveillance, lung macrophages often become co-opted by tumors to create an immunosuppressive environment that facilitates metastasis. Understanding the complex interactions between lung macrophages and metastatic cancer cells is critical for developing novel therapeutic strategies that target these immune cells and prevent the spread of cancer. By reprogramming macrophages, inhibiting their recruitment, or modulating their immune checkpoint activity, it may be possible to enhance anti-tumor immunity and improve outcomes for patients with metastatic cancer. Future research into the precise mechanisms of macrophage function in the metastatic niche, combined with the development of macrophagetargeted therapies, holds great promise in the fight against cancer. As we continue to uncover the intricate roles of macrophages in cancer metastasis, it is likely that new therapeutic avenues will emerge to combat this devastating disease.

Acknowledgment

None

Conflict of Interest

None

References

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