Dying cell clearance and its impact on the outcome of tumor radiotherapy

TLDR

Radiotherapy’s therapeutic success depends not only on direct tumor cell killing but also on innate and adaptive immune responses, with phagocytic clearance of dying tumor cells by dendritic cells and macrophages playing a pivotal role in shaping adaptive immunity. This review summarizes the various forms of ionizing radiation–induced cell death, the multi‑step clearance of dying tumor cells, and the resulting immunological consequences, with an eye toward exploiting these mechanisms to enhance radiotherapy. It examines how different radiation‑induced cell death pathways trigger phagocytic clearance and modulate innate and adaptive immune responses that can improve tumor control.

Abstract

The induction of tumor cell death is one of the major goals of radiotherapy and has been considered to be the central determinant of its therapeutic outcome for a long time. However, accumulating evidence suggests that the success of radiotherapy does not only derive from direct cytotoxic effects on the tumor cells alone, but instead might also depend - at least in part - on innate as well as adaptive immune responses, which can particularly target tumor cells that survive local irradiation. The clearance of dying tumor cells by phagocytic cells of the innate immune system represents a crucial step in this scenario. Dendritic cells and macrophages, which engulf, process and present dying tumor cell material to adaptive immune cells, can trigger, skew, or inhibit adaptive immune responses, respectively. In this review we summarize the current knowledge of different forms of cell death induced by ionizing radiation, the multi-step process of dying cell clearance, and its immunological consequences with special regard toward the potential exploitation of these mechanisms for the improvement of tumor radiotherapy.