Radiotherapy is a common cancer treatment, used in about half of all cancer patients, and involves delivering ionizing radiation to kill tumor cells while minimizing damage to normal tissues. It is used for curative intent or to relieve symptoms. Radiotherapy has evolved significantly since its first use in the late 19th century, with technological advancements leading to more precise delivery methods such as external beam radiotherapy, brachytherapy, and proton therapy. Radiotherapy aims to improve local control of tumors, often as part of a multimodal treatment approach. It can also be used to treat metastatic disease in some cases. Radiotherapy induces DNA damage, which can be repaired by various pathways. However, factors such as tumor hypoxia and the tumor microenvironment can affect its effectiveness. Radiotherapy can also suppress anti-tumor immunity by recruiting regulatory T cells, myeloid-derived suppressor cells, and suppressive macrophages. The balance of pro- and anti-tumor immunity is regulated by chemokines and cytokines induced by radiotherapy. Microbiota can also influence radiotherapy outcomes. Radiotherapy can enhance anti-tumor immunity by reprogramming the tumor microenvironment, triggering DNA and RNA sensing cascades that activate innate immunity and enhance adaptive immunity. However, it can also induce suppression of anti-tumor immunity. The immune contexture of the tumor may determine the effectiveness of radiotherapy, and recent studies have focused on exploiting the immune system with radiotherapy to improve therapeutic outcomes. Preclinical studies show that radiation induces acute inflammation and a complex response in the tumor microenvironment. Radiation can induce immunogenic cell death, generating neoantigens in tumor cells. Radiation leads to enhanced dendritic cell maturation and antigen presentation, followed by T cell priming. CD8⁺ T cells are essential for the optimal anti-tumor effects of radiotherapy. However, T cells can be quickly exhausted or limited by immune checkpoints induced by radiotherapy, such as PD-L1 and CTLA-4. Radiotherapy can also induce regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), which suppress CD8⁺ T cell responses and promote tumor growth. Radiotherapy can also induce overexpression of purinergic signaling, which contributes to radioresistance. The immune checkpoint pathways, such as PD-1/PD-L1 and CTLA-4, play a central role in inhibiting anticancer T cell immunity. Radiotherapy can increase the expression of PD-L1 on tumor cells, which can be targeted with immunotherapy. The cGAS/STING pathway is involved in the activation of innate immunity and IR-induced anti-tumor effects. However, the complexity of the cGAS/STING cascade may contribute to the negative results in clinical trials using STING agonists alone or in combination with other therapies. The purinergic signaling pathway is involved in radioresistance and can be a target for drug development. The microbiRadiotherapy is a common cancer treatment, used in about half of all cancer patients, and involves delivering ionizing radiation to kill tumor cells while minimizing damage to normal tissues. It is used for curative intent or to relieve symptoms. Radiotherapy has evolved significantly since its first use in the late 19th century, with technological advancements leading to more precise delivery methods such as external beam radiotherapy, brachytherapy, and proton therapy. Radiotherapy aims to improve local control of tumors, often as part of a multimodal treatment approach. It can also be used to treat metastatic disease in some cases. Radiotherapy induces DNA damage, which can be repaired by various pathways. However, factors such as tumor hypoxia and the tumor microenvironment can affect its effectiveness. Radiotherapy can also suppress anti-tumor immunity by recruiting regulatory T cells, myeloid-derived suppressor cells, and suppressive macrophages. The balance of pro- and anti-tumor immunity is regulated by chemokines and cytokines induced by radiotherapy. Microbiota can also influence radiotherapy outcomes. Radiotherapy can enhance anti-tumor immunity by reprogramming the tumor microenvironment, triggering DNA and RNA sensing cascades that activate innate immunity and enhance adaptive immunity. However, it can also induce suppression of anti-tumor immunity. The immune contexture of the tumor may determine the effectiveness of radiotherapy, and recent studies have focused on exploiting the immune system with radiotherapy to improve therapeutic outcomes. Preclinical studies show that radiation induces acute inflammation and a complex response in the tumor microenvironment. Radiation can induce immunogenic cell death, generating neoantigens in tumor cells. Radiation leads to enhanced dendritic cell maturation and antigen presentation, followed by T cell priming. CD8⁺ T cells are essential for the optimal anti-tumor effects of radiotherapy. However, T cells can be quickly exhausted or limited by immune checkpoints induced by radiotherapy, such as PD-L1 and CTLA-4. Radiotherapy can also induce regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), which suppress CD8⁺ T cell responses and promote tumor growth. Radiotherapy can also induce overexpression of purinergic signaling, which contributes to radioresistance. The immune checkpoint pathways, such as PD-1/PD-L1 and CTLA-4, play a central role in inhibiting anticancer T cell immunity. Radiotherapy can increase the expression of PD-L1 on tumor cells, which can be targeted with immunotherapy. The cGAS/STING pathway is involved in the activation of innate immunity and IR-induced anti-tumor effects. However, the complexity of the cGAS/STING cascade may contribute to the negative results in clinical trials using STING agonists alone or in combination with other therapies. The purinergic signaling pathway is involved in radioresistance and can be a target for drug development. The microbi