Molecular landscape and clinical translation of DNA damage response alterations in solid tumors: A pan-cancer perspective on precision oncology

DNA damage response (DDR) pathways are essential for maintaining genomic integrity. Accumulating pan-cancer evidence, however, reveals that alterations within these networks act as widespread drivers of tumor initiation, progression, and therapeutic vulnerability. This review synthesizes the biological mechanisms and clinical implications of DDR defects across solid tumors. We first detail how the disruption of major DDR pathways leads to profound genomic instability and characteristic mutational heterogeneity. Building on this mechanistic foundation, we evaluate the interaction between DDR deficiencies and the tumor immune microenvironment to highlight emerging opportunities for immunotherapy. We also critically examine recent advances in targeted treatment paradigms based on synthetic lethality, focusing particularly on the evolving clinical landscape of PARP inhibitors. Finally, we link these biological insights directly to clinical practice by discussing genetic risk assessment, biomarker development, and precision therapeutic decision-making. Ultimately, a deeper understanding of these alterations is essential to develop more effective targeted and combinatorial therapies for patients with DDR-deficient malignancies.