Synthetic reprogramming of tumor cell fate for modulating radiotherapy-induced dynamic responses: perspectives on radiosensitizing and immunoregulatory effects

Radiotherapy is one of the most commonly prescribed anticancer modalities in the clinic, which is widely recognized as an effective and safe treatment for a broad spectrum of solid tumor indications. Interestingly, there is increasing evidence that the tumors can dynamically modulate cell fate decisions after ionizing radiation (IR) exposure, which is beneficial for escaping the radiation-induced antitumorigenic cell damaging and immunostimulatory impacts. Consequently, the regulatory network of cell fate determination could be a promising target for enhancing the susceptibility of tumor cells to various radiotherapeutic modalities. In this review, we provide a comprehensive account on the mechanisms of post-radiation cell fate control in tumor cells to escape programmed cell death (PCD) including apoptosis, necrosis, pyroptosis and ferroptosis, while special emphasis is placed on the development of synthetic agents for the therapeutic modulation of post-radiation tumor cell fate decisions to facilitate tumor cell eradication, focusing on their therapeutic utility for amplifying the RT-induced direct tumor cell damage as well as promoting the post-IR antitumor immunity. We envision that these synthetic cell fate regulatory technologies could provide new avenues for improving radiotherapeutic efficacy.