Radiation therapy is a cornerstone of modern cancer therapy. Alongside surgery, chemotherapy and molecularly-targeted therapeutics, radiation therapy comprise the treatment regimen of over half of all cancer patients (Schaue & McBride, 2015). Radiotherapy approach is based on the use of various types of radiation include external beam radiation therapy (EBRT) using high-energy photons, electrons, or protons, as well as brachytherapy and radionuclide therapy. Radiation therapy deposits focal radiation to the tumor and surrounding at-risk tissue compartments such as regional lymph nodes to inhibit growth, proliferation and metastasis of tumor cells (Lu, Guo, Wei, Zheng, & Li, 2023). Classic dogma in radiobiology suggests that upon interaction with tissue, radiation directly damages cellular DNA through double-stranded breaks (DSBs); or indirectly results in formation of reactive oxygen species (ROS) following radiolysis of water molecules (Lu et al., 2022, Ouellette et al., 2022). Therapeutic effects lead to cell death such as apoptosis, necrosis, senescence and abnormal mitosis of the tumor cells (Kuwahara et al., 2018) but also in a large number of exposed non-tumor cells in tumor microenvironmental (TME) (Wu & Dai, 2017). Despite all the positive antineoplastic effects of radiation therapy, some of the patients show a therapeutic failure. Radioresistance is the most common cause of tumor recurrence or disease progression, and is closely associated with an increase in cancer mortality. Radiotherapy failure allow cancer cell survival and subsequent tumor growing (Kim et al., 2015, Larionova et al., 2022, Miller et al., 2022).

Failure of radiotherapy is due to the inherent genetic characteristics of cancer cells or acquired resistance after radiation exposure (Liu et al., 2021). Radioresistance is a multifactorial phenomenon involved numerous molecular mechanisms of action including activation of DNA repair processes, cell survival and proliferation, apoptosis resistance, hypoxia, senescence, alterations of cell growth and cell cycle, increase in invasiveness and migration capacity, among others (Ouellette et al., 2022). Also, molecular radioresistance comprises different regulatory molecules and pathways that are distinctive of tumor cell types. In particular, cancer stem cells (CSCs) are postulated to represent a radiation-resistant subpopulation within tumors contributing to repopulate the tumor following radiation therapy (Arnold, Mangesius, Skvortsova, & Ganswindt, 2020). Furthermore, resistance of the cancer cells include the complex communication with non-tumor cells in the TME as stromal cells and immune cells throughout the mechanism of back-and-forth communication between tumor and non-tumor cells (Wu & Dai, 2017). Therefore, radiation activate several mechanisms to regulate pathways of radioresistance in both cancer cells (differentiated cancer cells and cancer stem cells) and non-tumor cells (stroma cells and immune cells) within tumor (Suwa, Kobayashi, Nam, & Harada, 2021). Epigenetic mechanisms are one of the most relevant events that occur after radiotherapy resulting in aberrant gene expression and favoring pathways of radiation resistance (Khan et al., 2022, Peng et al., 2021, Wang et al., 2022). This review highlights epigenetic modifications that regulate the most relevant signaling pathways related to radiation therapy response in cancer.