Targeting DNA Damage Response and Immune Crosstalk in Cancer: Mechanistic Insights and Therapeutic Opportunities

Cancer progression and therapeutic resistance are driven by complex molecular interactions between genomic instability and immune modulation. Defects in the DNA damage response (DDR) not only promote tumor heterogeneity but also shape the tumor immune landscape through the generation of neoantigens, activation of the cGAS-STING pathway, and modulation of immune checkpoints. This review provides an integrative overview of the molecular mechanisms linking DDR dysfunction to immune crosstalk, emphasizing how these processes influence tumor evolution and response to therapy. We discuss emerging therapeutic strategies that exploit DDR-immune interactions, including PARP and ATR inhibitors, synthetic lethality approaches, and combination regimens with immune checkpoint blockade. Understanding the bidirectional connection between DNA repair pathways and immune signaling unveils new translational opportunities for precision oncology and offers a framework for developing combinatorial therapies capable of overcoming resistance and improving long-term cancer control.