Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors

Abstract Long-term toxicities caused by cancer treatments have recently gained increasing recognition due to a steadily growing population of cancer survivors. Radiotherapy (RT) is a common treatment known to unintentionally harm surrounding normal tissuesincluding the skin, hindering wound healing even years after treatment. Our study aimed to elucidate the underlying mechanisms of these late-onset adverse effects caused by RT. By comparing paired skin biopsies from previously irradiated (RT + ) and non-irradiated (RT − ) sites in breast cancer survivors who underwent RT years ago, we discovered compromised wound healing capacity and impaired fibroblast functions in the RT + skin. By employing ATAC-seq, we identified altered chromatin landscapes in RT + fibroblasts, pinpointing THBS1 as a crucial epigenetically primed wound repair-related gene. Further confirmation of THBS1's significance during wound repair came from single-cell RNA-sequencing and spatial transcriptomic analysis of human wounds. Remarkably, heightened and sustained THBS1 expression was observed in RT + fibroblasts in both mouse and human radiation wound models, leading to impaired fibroblast motility and contractility. Encouragingly, our study found that treatment with anti-THBS1 antibodies promoted ex vivo wound closure in RT + skin from breast cancer survivors. These findings indicate that dermal fibroblasts retain a long-term radiation memory recorded in the form of epigenetic changes. Targeting this maladaptive epigenetic memory shows promise for mitigating the late-onset adverse effects caused by RT, offering potential solutions to improve the quality of life for cancer survivors.