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. 2021 Apr 9;10(4):862. doi: 10.3390/cells10040862

Table 1.

A summary of Therapeutic Strategies Targeting the Hypoxic Melanoma Microenvironment.

The Therapeutic Approach Treatment Description Results and Utilized Research Model
Indirect targeting
(angiogenesis)
Anti-VEGF antibodies
and multikinase inhibitors
Phase I/II of clinical trials for novel drug combinations are still ongoing. Monotherapies were not effective, while combination treatment with chemotherapy induced short-term response [130].
sVEGFR (vector or induced by GM-CSF) Reduction of tumor angiogenesis, growth, and metastasis was observed in vitro and using murine melanoma model [131,132].
Promotion of endothelial gap junctions (Sac-1004) In murine melanoma model, vasculature normalization, inhibition of metastasis and EMT, reduction of cancer stem-like cells population was noted [133].
Direct targeting
(HIF-1α inhibitors)
Acriflavine Inhibitors blocked the metabolism and proliferation of melanoma cells in vitro [134].
2-methoxyestradiol Drug resensitized radioresistant cells and partially suppressed their glycolytic state [135].
Cinnamaldehyde Treatment reduced the invasiveness of melanoma cells in vitro and in vivo [136].
Arylsulfonamide (64B) The compound decreased the growth and metastasis of murine uveal melanoma [8].
Direct targeting
(alleviation of
hypoxic conditions)
Metformin (inhibition of oxygen consumption) Improvement of anti-PD-L1 therapy was observed in murine melanoma model [137].
Liposomes with hemoglobin and doxorubicin, followed by radiotherapy Treatment efficiently blocked migration in vitro and inhibited tumor growth in mice [138].
Multimodal platforms (CAT@aPDL1-SSL, mZDC, Au@MTM-HA) Treated mice exhibited improved tumor infiltration by cytotoxic T cells, prolonged survival, and reduced metastasis rate [139,140,141].
Direct targeting
(oxygen-sensitive treatment)
Prodrugs activated in hypoxia
(tirapazamine, TH-302)
Combination therapy resulted in effective tumor size reduction in mice [142,143].
Bacteria as drug delivery vectors
(S. typhimurium) or
oncolytic inducers (C. novyi-NT)
Bacteria-delivered vector reduced the proliferation of melanoma cells, while the oncolytic strain efficiently targeted solid tumors [144,145].

VEGF, vascular endothelial growth factor; sVEGFR, soluble vascular endothelial growth factor receptor; GM-CSF, granulocyte-macrophage colony-stimulating factor; EMT, epithelial-to-mesenchymal transition; HIF-1α, hypoxia-inducible factor 1α; PD-L1, programmed cell death ligand 1.