Abstract:

Radiotherapy-induced late effects (RILE) or delayed reactions have significant impacts on patients' long-term quality of life. However, current understanding of their developmental mechanisms remains limited, with a lack of effective risk prediction models and preventive interventions. Radiobiological studies and radiation-induced senescence models have revealed that radiotherapy can alter the epigenetic characteristics in late-responding tissue cells, leading to derepression of retrotransposable elements (particularly endogenous retroviral elements), subsequent activation of cytoplasmic nucleic acid sensor systems (cGAS-STING, MDA5/RIG-I-MAVS) and type Ⅰ interferon-mediated immune-inflammatory responses. This review summarized relevant research findings, proposing that the autoimmune-like inflammatory response induced by the 'radiotherapy-epigenetic alteration-retrotransposable element activation’ cascade is an underinvestigated mechanistic basis in the development of RILE. Constructing risk prediction models for late effects based on epigenetic signatures, cell type, and radiation dose, along with developing strategies to epigenetically suppress retrotransposable element expression, holds promise for preventing or mitigating RILE.

Key words: Radiotherapy, Late effect, Late-responding tissues, Retrotransposable elements, Autoimmune inflammation