Sequential light irradiation-controlled cancer stemness inhibition for sensitized photothermal therapy

Abstract

Cancer stem-like cells (CSCs) have a well-established role in mediating tumor relapse and resistance towards chemotherapy and radiation therapy. Photothermal therapy (PTT) is an efficient therapeutic strategy that uses light and photothermal agents to generate hyperthermia in tumors and kill cancer cells. However, due to the heterogeneity and drug resistance of CSCs, some of them may survive from PTT and cause recurrence and metastasis of tumors. In the study, we present a sequential dual-wavelength light-controlled drug delivery strategy, which combines 656 nm light-triggered drug release to inhibit cancer stemness, followed by 808 nm light-activated PTT to eradicate bulk tumors. The first light irradiation induces the release of γ-secretase inhibitor MK-0752 to deactivate Notch pathway, which is a key regulator of CSCs. Subsequently, the second light irradiation triggers hyperthermia to effectively kill tumor cells. Our findings demonstrate that inhibiting cancer stemness increases tumor sensitivity to PTT, resulting in effective growth inhibition of primary tumors with repressed tumorgenicity. This innovative dual-wavelength strategy holds promise for enhancing the efficacy of PTT in addressing the challenges posed by CSCs-rooted heterogeneity and drug resistance.