Harnessing Genomic Stress for Antitumor Immunity

Genomic instability, a hallmark of cancer, renders cancer cells susceptible to genomic stress from both endogenous and exogenous origins, resulting in the increased tendency to accrue DNA damage, chromosomal instability, or aberrant DNA localization. Apart from the cell autonomous tumor-promoting effects, genomic stress in cancer cells could have a profound impact on the tumor microenvironment. Recently, it is increasingly appreciated that harnessing genomic stress could provide a promising strategy to revive antitumor immunity, and thereby offer new therapeutic opportunities in cancer treatment. Genomic stress is closely intertwined with antitumor immunity mechanisms involving the direct crosstalk with DNA damage response components, upregulation of immune-stimulatory/inhibitory ligands, release of damage-associated molecular patterns, increase of neoantigen repertoire, and activation of DNA sensing pathways. A better understanding of these mechanisms will provide molecular basis for exploiting the genomic stress to boost antitumor immunity. Future research should pay attention to the heterogeneity between individual cancers in the genomic instability and the associated immune response, and how to balance the toxicity and benefit by specifying the types, potency, and treatment sequence of genomic stress inducer in therapeutic practice. 34, 1128-1150.