An Emerging Regulatory Role for the Tumor Microenvironment in the DNA Damage Response to Double-Strand Breaks

Abstract

Radiation, alkylating agents, and platinum-based chemotherapy treatments eliminate cancer cells through the induction of excessive DNA damage. The resultant DNA damage challenges the cancer cell's DNA repair capacity. Among the different types of DNA damage induced in cells, double-strand breaks (DSB) are the most lethal if left unrepaired. Unrepaired DSBs in tumor cells exacerbate existing gene deletions, chromosome losses and rearrangements, and aberrant features that characteristically enable tumor progression, metastasis, and drug resistance. Tumor microenvironmental factors like hypoxia, inflammation, cellular metabolism, and the immune system profoundly influence DSB repair mechanisms. Here, we put into context the role of the microenvironment in governing DSB repair mechanisms.

Figure 1.

DSBs-inducing agents used for the treatment of cancer.

Figure 2.

Cellular DSBs are repaired mainly through HR and NHEJ; both mechanisms involve distinct repair proteins. Tumor microenvironment factors like hypoxia, inflammation, immune cells, genotoxic stress, and cellular metabolites influence the DSB repair in the cell.

Figure 3.

The solid tumor microenvironment comprising hypoxia, inflammation, and immune cells impact DSB repair pathways in cancer cells. The diagrams were drawn using motifolio drawing toolkits (www.motifolio.com). A. In DCs, the presence of dsDNA activates the cGAS-STING pathway and leads to activation of IRF-3 and NF-kB enhancing the pro-inflammatory immune response. B. DSB-mediated expression of cellular cytokines, chemokines, and crosstalk between stromal cells in the solid tumor microenvironment serves important function in immune cell homing and migration.