Precision Radiation Oncology: Molecular Strategies to Enhance Anti-Tumour Responses to Radiotherapy—Beyond Direct Tumour Cell Killing

Radiotherapy remains a cornerstone of cancer treatment, yet treatment response continues to be limited by tumour radioresistance and considerable biological heterogeneity. Although advances in radiation delivery have substantially improved dose conformity and reduced toxicity, increasing evidence suggests that optimising therapeutic outcomes will require greater integration of tumour biology into treatment strategies. This review examines emerging molecular approaches that seek to enhance anti-tumour responses to radiotherapy beyond direct tumour cell killing. We discuss the DNA damage response as a therapeutic target for radiosensitisation, highlighting the evolving role of DNA damage response inhibitors in promoting both tumour cytotoxicity and immune activation. We further examine the mechanisms linking radiation-induced DNA damage to anti-tumour immunity, including immunogenic cell death, cGAS–STING signalling, and remodelling of the tumour microenvironment, together with the opportunities and challenges of combining radiotherapy with immune checkpoint inhibition. Finally, we review emerging concepts in precision radiation oncology, including spatially tailored irradiation strategies, genomically informed radiation prescription, radiogenomics, and the influence of the gut microbiome on treatment response. Collectively, these advances support a shift from anatomically guided radiotherapy towards biologically personalised treatment, integrating molecular, immunological and genomic information with normal-tissue susceptibility to improve the therapeutic ratio and enable more precise, patient-centred cancer care.