Table 3.

Cytokines reported to have a role in melanoma brain metastases.

Cytokine	Role	Model	Reference
IL-17A	Promotes angiogenesis and induces IL-6 production	In vitro	[69]
CXCL10	Modulates the migration of monocytes, macrophages, T cells, and NK cells to the brain	In vivo (mouse)	[70]
CCL17	Increases tumorigenicity and micrometastasis formation in the brain	In vivo (mouse)	[71]
CCL2	Recruits cytotoxic T lymphocytes to the metastatic melanoma site and induces an immune-mediated protective role	In vitro	[72]
	Recruits myeloid cells that prime the growth of metastatic melanoma cells in the brain	Patient samples	[73]
CCL22	Regulates the AKT phosphorylation pattern and subsequent tumor cell survival and proliferation	Patient samples	[74]
IL-6	Induces the production of GSH in melanoma cells, facilitating their growth in the brain	In vivo (mouse)	[75]
	Triggers MMP-2 enzymatic activity in the tumor microenvironment	In vitro	[76]
IL-8	Increases melanoma cell migration, invasion, and adhesion capacities, and activates MAPK signaling pathway	In vivo (mouse)	[77]
	Induces VEGFA-mediated angiogenesis and vascular co-option controlled by MMP-2 and MMP-9	In vivo (mouse)	[78]
TNF-α IFN-γ	Enhances the invasion of metastatic melanoma cells and increases tumor cell aggressiveness	In vitro	[76]
VEGF Eotaxin RANTES IL-12	Trigger MMP-2 enzymatic activity that enhances the invasion of metastatic melanoma cells and increases tumor cell colonization	In vitro	[76]
IL-33	Binds to ST2 receptor and induces melanoma proliferation, migration, and invasion through MMP-2, MMP-9, and ERK1/2 phosphorylation	Patient samples	[79]
IL-1β	Induces VEGF production by endothelial cells, modulating the inflammatory brain microenvironment of the tumor and enhancing angiogenesis and tumor progression	In vivo (mouse)	[80]
IFN-α2β	Inhibit lymphangiogenesis-mediated melanoma metastasis by decreasing VEGF-C and VEGF receptor-3 expression	In vivo (mouse)	[81]
IFN-β1α
IFN-α	Enhances both innate and adaptive cytotoxic T-cell activities	In vivo (mouse)	[82]
SOCS-1	Inhibits Stat3 signaling and downregulates MMP-2, bFGF, and VEGF, leading to decreased invasion and angiogenesis	Patient samples	[83]
IL-23	Upregulates MMP-2 to facilitate melanoma cell migration and invasion into the brain parenchyma	In vivo (mouse)	[84]
TGF-β	Induces tolerance of melanoma cells against T cell cytotoxicity	In vitro (mouse)	[85]
	Plays a pivotal role in the spatial distribution of melanoma cells in the brain parenchyma	In vivo (mouse)	[86]