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Radiotherapy is a crucial treatment option for various cancers. However, the results of radiotherapy can vary widely across different cancer types and even among patients with the same type of cancer. This variability presents a major challenge in optimizing treatment strategies and improving patient survival. Here, we collected radiotherapy phenotype and expression data from 32 TCGA cancer datasets and performed overall survival analysis for 32 cancer types. Additionally, we conducted a signaling pathway enrichment analysis to identify key pathways involved in radiotherapy resistance and sensitivity. Our findings show that radiotherapy improves survival outcomes in certain cancer types, such as glioblasoma multiforme (GBM), while worsening outcomes in others, such as low-grade glioma (LGG). Next, we focused on exploring the differences in radiotherapy outcomes between GBM and LGG, focusing on the molecular mechanisms contributing to these variations. We identify differential regulation of pathways related to programmed cell death, DNA repair, telomere maintenance, chromosome condensation, antiviral responses, and interferon signaling between GBM and LGG patients perhaps explaining radiotherapy efficacy. A genetic analysis confirmed the importance of immune response and radiotherapy outcome for LGG patients. These insights underscore the importance of personalized treatment approaches and the need for further research to improve radiotherapy outcomes in cancer patients.