Radiotherapy causes DNA damage by direct ionization and indirect generation of
reactive oxygen species (ROS) thereby destroying
cancer cells. However, ionizing radiation (IR) unexpectedly elicits
metastasis and invasion of
cancer cells by inducing cancer stem cells' (CSCs) properties. As BMI1 is a crucial gene that causes radioresistance and an unfavorable prognosis of
hepatocellular carcinoma (HCC), BMI1 inhibitor
PTC-209 has been encapsulated in a ROS-responsive
liposome (LP(PTC-209)) to be temporally and spatially delivered to radioresistant HCC tissue. The ROS generated during IR was not only considered to directly cause
tumor cell death but also be used as a stimulator to trigger ROS-responsive drug release from LP(PTC-209). The
PTC-209 released into resistant HCC tissue under
radiotherapy further led to cancer stem cell (CSC) differentiation and then recovered radiosensitivity of HCC
tumor. The suppression of the radioresistant performance of LP(PTC-209) has been proved on radiosensitive and radioresistant Hepa1-6 CSC
tumor models, respectively. Our study clarified the relationship between
radiotherapy and
cancer stemness and provided insights to achieve complete suppression of radioresistant HCC
tumor by inhibiting
cancer stemness.