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.