Blue light promotes vitamin C-mediated ferroptosis of melanoma through specifically upregulating transporter SVCT2 and generating Fe.

Vitamin C (VC)-based cancer therapy is a promising therapeutic approach for a variety of cancers due to its profound effects on redox reactions and metabolic pathways. However, high administration dosage of VC for necessary therapeutic efficacy for cancers increases the risk of overt side effects and limits its clinical use. Here, we show cutaneous blue light irradiation can specifically upregulate the sodium-dependent vitamin C transporter 2 (SVCT2) of the tumor and increase effectively the VC concentration at the tumor sites by an overall low dosage administration. In the mouse melanoma model, blue light stimulates the SVCT2 expression through the nuclear factor-kappa B (NF-κB) signaling pathway both in vitro and in vivo. The increased cellular VC together with Fe generated by blue light simultaneously elevate cellular oxidative stress and trigger the ferroptosis of melanoma. With this revealed mechanism, the synergistic actions of blue light on the VC transporter and Fe generation lead to a ca. 20-fold reduction in the administration dosage of VC with an effective melanoma elimination and prolonged survival. The work defines the killing mechanism of blue light on VC-based cancer therapy and provides a practical approach for promoting VC uptake. This light-assisted VC therapy is not only highly efficient for melanoma but also considerable for a broad clinical utility.