Why Macrophages Play Opposite Roles in Cancer

Macrophages are key players in the immune system, involved in maintaining tissue homeostasis and responding to infections. However, in the context of cancer, macrophages assume complex and often contradictory roles, contributing to both tumor suppression and tumor promotion. Studies have found that macrophages can significantly influence the tumor microenvironment (TME) by secreting a variety of factors and interacting with other immune cells.

On the one hand, macrophages can cause chronic inflammation, thereby initiating or promoting tumor development. They secrete tumor-promoting factors such as ornithine, vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and transforming growth factor-β (TGF-β). These molecules support a variety of pro-tumor processes, including angiogenesis (the formation of new blood vessels to provide nutrients to tumors), tumor cell proliferation, and immune suppression. For example, VEGF is critical for the formation of new blood vessels that contribute to tumor growth and metastasis, while TGF-β and EGF enhance the invasiveness of tumor cells.

On the other hand, macrophages also have the ability to suppress tumors. They can produce nitric oxide (NO) via inducible nitric oxide synthase (iNOS), which has been shown to inhibit tumor growth by inducing oxidative stress and apoptosis in tumor cells. Despite these tumor-suppressive effects, the overall impact of macrophages in cancer is often biased toward promoting tumor progression, primarily due to their adaptation to the TME.

Furthermore, macrophages are involved in regulating key features of malignancy, including cancer cell invasiveness, metastasis, and treatment resistance. By regulating immune responses and the behavior of other immune cells, macrophages play a central role in shaping the tumor microenvironment, often enabling cancer cells to evade immune surveillance and resist conventional treatments.

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References

[1] Zhaojun Duan and Yunping Luo, Signal Transduction and Targeted Therapy 2021 (https://doi.org/10.1038/s41392-021-00506-6 )

[2] Paulina Pathria et al., Trends in Immunology 2019; 40: 310-27