Why nutrients?

It is well known that nutrients are involved in maintaining the metabolism of organisms, including tumours. During the culturing of melanoma B16F10 cells, we observed an interesting phenomenon: melanoma cells grew well for dozens of passages in RPMI 1640 medium, but they grew slowly in DMEM medium accompanied by significant pigmentation. This phenomenon has been confirmed in three other types of melanoma cells. We attributed this to the high level of L-Tyrosine, the precursor of melanin, in DMEM. Supplementing L-Tyrosine in RPMI 1640 medium resulted in melanoma cells growing more slowly with pigmentation. This simple experiment illustrates an antagonistic effect between melanin pigmentation and the proliferation of melanoma cells. Literature review revealed that melanogenesis is downregulated in melanoma cells compared to melanocytes, and patients with a low ssGSEA score in “KEGG melanogenesis” are correlated with worse 5-year survival outcomes. These findings suggest that promoting melanin anabolism can trigger an inhibitory effect on melanoma cells. Therefore, we propose a strategy of reactivating the inversely regulated metabolic pathways for tumour treatment using nutrients, such as Tyrosine, as metabolism activators.

How to supplement nutrients?

An important factor driving the success of our work is the use of nanotechnology for nutrients delivery. Due to the limited intake of free nutrients by tumour cells, supplementation with free nutrients may not be efficient for tumour suppression. We developed a type of L-Tyrosine-based nanomicelle (MTyr-OANP) to improve the low targeting efficiency of free nutrients. This method has resulted in a three-fold increase in melanin synthesis and secretion compared to conventional tyrosine supplementation. The heightened activity and expression of melanin synthesis-related enzymes significantly stimulate melanosome synthesis.

Investigation of the anti-tumour mechanism

MTyr-OANPs have been found to inhibit the growth of melanoma cells, all with increased total melanin and tyrosinase activity. MTyr-ONAPs inhibited melanoma cell migration and downregulated the expression of MMP2 and MMP9, indicating that continuous L-tyrosine stimulation induced melanin synthesis may not trigger metastasis like other melanogenesis promoting stimulus, such as UV radiation. Melanogenesis reactivation with MTyr-OANPs prominently retarded melanoma cell proliferation through glycolysis inhibition. We demonstrated that reduced glycolysis was a consequence of pyruvate kinase (PKM) inhibition by melanin intermediates indole-5,6-quinone.

 How is the efficiency?

Excitingly, the study revealed that tyrosine nanomicelles exhibit a remarkable efficiency rate of 4.4% in targeting melanoma in vivo, showing substantial anti-tumour effects across various melanoma types, including BRAF mutant and wild-type tumours. The treatment displayed heightened efficacy against BRAF wild-type tumours, potentially linked to the observed over-ubiquitination of MITF, a key regulator of melanin synthesis in BRAF mutant melanomas. Moreover, abundant melanogenesis resulted in significant phenotypes changes in melanoma cells, making these cells vulnerable to NIR laser treatment due to pigmentation and the downregulation of heat shock proteins (HSP 70 and HSP 90). These findings lay a robust foundation for the clinical application of this cutting-edge nutrients nanomedicine.