The role of mitochondria in the resistance of melanoma to PD-1 inhibitors

Abstract

Malignant melanoma is one of the most common tumours and has the highest mortality rate of all types of skin cancers worldwide. Traditional and novel therapeutic approaches, including surgery, targeted therapy and immunotherapy, have shown good efficacy in the treatment of melanoma. At present, the mainstay of treatment for melanoma is immunotherapy combined with other treatment strategies. However, immune checkpoint inhibitors, such as PD-1 inhibitors, are not particularly effective in the clinical treatment of patients with melanoma. Changes in mitochondrial function may affect the development of melanoma and the efficacy of PD-1 inhibitors. To elucidate the role of mitochondria in the resistance of melanoma to PD-1 inhibitors, this review comprehensively summarises the role of mitochondria in the occurrence and development of melanoma, targets related to the function of mitochondria in melanoma cells and changes in mitochondrial function in different cells in melanoma resistant to PD-1 inhibitors. This review may help to develop therapeutic strategies for improving the clinical response rate of PD-1 inhibitors and prolonging the survival of patients by activating mitochondrial function in tumour and T cells.

Keywords: Combined therapy; Drug resistance; Melanoma; Mitochondria; PD-1 inhibitor.

Fig. 1

Mechanism of melanoma resistance to PD-1 inhibitors. The main mechanisms of melanoma resistance to PD-1 inhibitors include: (1) Insufficient immunogenicity of tumor; (2) MHC dysfunction caused by B2M mutation; (3) CD8⁺T cells transformed into depleted T cells (Tex) due to continuous stimulation of tumor antigen; (4) IFN- γ signal plays an immunosuppressive role; (5) interference from other cells in tumor microenvironment. MHC: Major histocompatibility complex; B2M: β 2-microglobulin; APC: Antigen-presenting cells; STAT: Signal transducer and activator of transcription; JAK: Janus Kinase; TAM: Tumor-associated macrophages; MDSC: Myeloid-derived suppressor cells

Fig. 2

Metabolic changes in melanoma cells affect cell proliferation, migration and therapeutic resistance. When normal cells are transformed into melanoma cells, intracellular mitochondrial metabolism is weakened and glycolysis is enhanced, which will promote tumor cell proliferation, migration and therapeutic resistance

Fig. 3

The relationship between the occurrence and development of melanoma cells and mitochondria. Activation and mutation of NRAS or BRAF genes in MAPK and PI3K signaling pathways in melanoma cells can inhibit mitochondrial function and promote glycolysis. The increase of intracellular calcium concentration in melanoma cells can inhibit the function of mitochondria. In addition, some miRNAs may also affect the function of mitochondria. PI3K: Phosphatidylinositol 3-kinase; MAPK: Mitogen-activated protein kinases; NADH: Nicotinamide adenine dinucleotide; HIF1α: Hypoxia inducible factor-1α; mTOR: mammalian Target of rapamycin; PDK1: Phosphoinositide-dependent protein kinase 1; PTEN: Phosphatase and tensin homolog; NRAS: Neuroblastoma RAS; MAPK: Mitogen-activated protein kinase; MITF: Microphthalmia-associated transcription factor; NRF1: Nuclar respiratory factor-1; TFAM: Mitochondrial transcription factor A; MYC: Myelocytomatosis viral oncogene; Drp1: Dynamin-related protein 1; MDIVI-1: Mitochondrial division inhibitor 1

Fig. 4

Changes of mitochondrial function in different cells during drug resistance of melanoma TME. Melanoma cells, Tumor-MDSCs, and TAMs can all express PD-L1, which makes CD8⁺ T cells in a resting state. Among them, the expression of PD-L1 in melanoma cells is related to the JAK1/2-STAT pathway involved in mitochondria, while the expression of PD-L1 in TAM may be related to the PI3K γ-NF κ B pathway. When CD8⁺T cells receive dual-signal stimulation from melanoma cells, they can release IFN- γ to participate in immune regulation. After receiving the extracellular carrier (EV) released by melanoma cells, TAMS also releases interferon-γ and IL-6 to inhibit the immune function of T cells. In addition, melanoma cells can inhibit T cell aggregation by producing VEGF and IL-8 through the MAPK pathway, affecting their mitochondria’s function through the PI3K pathway. Tumor-MDSCs: Tumor-associated myeloid-derived suppressor cells; TAM: Tumor-associated macrophages; IFN- γ: Interferon-gamma; VEGF: Vascular endothelial growth factor; IDO-1: Indoleamine 2,3-Dioxygenase-1; EV: Extracellular vesicle