Radiotherapy, a treatment for cancer that involves the use of ionizing radiation (IR) to kill tumor cells while minimizing damage to healthy tissues, has evolved significantly over the past century. The primary focus of radiotherapy has shifted from DNA damage to the role of the immune system in enhancing anti-tumor effects. Radiotherapy reprograms the tumor microenvironment, activating innate and adaptive immune responses. However, it also suppresses anti-tumor immunity by recruiting regulatory T cells, myeloid-derived suppressor cells, and suppressive macrophages. The balance between pro- and anti-tumor immunity is regulated by chemokines and cytokines, and the microbiota can influence radiotherapy outcomes. Preclinical studies show that radiation induces acute inflammation and complex responses in the tumor microenvironment, leading to increased T-lymphocyte infiltration and neoantigen expression. CD8+ T cells are crucial for the optimal anti-tumor effects of radiation, but they can be exhausted or limited by immune checkpoints such as PD-L1 and CTLA-4. Radiation-induced regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) contribute to radioresistance by suppressing CD8+ T cell responses. TGF-β signaling is another important factor in radioresistance, promoting tumor progression and immune suppression. The purinergic signaling pathway, involving ATP and adenosine, plays a significant role in radioresistance by promoting cancer cell proliferation, migration, and epithelial-to-mesenchymal transition (EMT). Immune checkpoint pathways, particularly the PD-L1/PD-1 axis, are central to immune resistance during cancer treatment. Clinical trials combining radiotherapy with immune checkpoint inhibitors (ICIs) have shown mixed results, with some trials demonstrating improved outcomes in early-stage and locally advanced cancers, while others have been negative. Recent advancements in nanotechnology, such as nanoparticles and bispecific antibodies, have shown promise in enhancing the efficacy of radiotherapy and ICB combinations. Preclinical data suggest that these technologies can improve the anti-tumor immune response and reduce side effects. However, further research is needed to optimize these approaches for clinical use. Overall, the integration of radiotherapy with immunotherapy represents a promising strategy to enhance the effectiveness of cancer treatment, but challenges remain in understanding and overcoming mechanisms of immune suppression and radioresistance.Radiotherapy, a treatment for cancer that involves the use of ionizing radiation (IR) to kill tumor cells while minimizing damage to healthy tissues, has evolved significantly over the past century. The primary focus of radiotherapy has shifted from DNA damage to the role of the immune system in enhancing anti-tumor effects. Radiotherapy reprograms the tumor microenvironment, activating innate and adaptive immune responses. However, it also suppresses anti-tumor immunity by recruiting regulatory T cells, myeloid-derived suppressor cells, and suppressive macrophages. The balance between pro- and anti-tumor immunity is regulated by chemokines and cytokines, and the microbiota can influence radiotherapy outcomes. Preclinical studies show that radiation induces acute inflammation and complex responses in the tumor microenvironment, leading to increased T-lymphocyte infiltration and neoantigen expression. CD8+ T cells are crucial for the optimal anti-tumor effects of radiation, but they can be exhausted or limited by immune checkpoints such as PD-L1 and CTLA-4. Radiation-induced regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) contribute to radioresistance by suppressing CD8+ T cell responses. TGF-β signaling is another important factor in radioresistance, promoting tumor progression and immune suppression. The purinergic signaling pathway, involving ATP and adenosine, plays a significant role in radioresistance by promoting cancer cell proliferation, migration, and epithelial-to-mesenchymal transition (EMT). Immune checkpoint pathways, particularly the PD-L1/PD-1 axis, are central to immune resistance during cancer treatment. Clinical trials combining radiotherapy with immune checkpoint inhibitors (ICIs) have shown mixed results, with some trials demonstrating improved outcomes in early-stage and locally advanced cancers, while others have been negative. Recent advancements in nanotechnology, such as nanoparticles and bispecific antibodies, have shown promise in enhancing the efficacy of radiotherapy and ICB combinations. Preclinical data suggest that these technologies can improve the anti-tumor immune response and reduce side effects. However, further research is needed to optimize these approaches for clinical use. Overall, the integration of radiotherapy with immunotherapy represents a promising strategy to enhance the effectiveness of cancer treatment, but challenges remain in understanding and overcoming mechanisms of immune suppression and radioresistance.