Targeting replication stress in glioblastoma: From genotoxic treatment and inhibitors of the DNA damage response to immunotherapy.

Replication stress (RS) encompasses states of impaired DNA replication progression associated with fork slowing, stalling, or collapse. RS triggers a specialized branch of the DNA damage response (DDR) called the RS response (RSR) and constitutes a major source of genomic instability, which is a key hallmark of cancer. Cancer cells face high basal levels of RS due to sustained proliferative signaling. Besides endogenous stimuli, RS can be induced by exogenous sources such as chemotherapeutic drugs. In glioblastoma (GBM), the most aggressive primary brain tumor, chronic RS leading to DDR activation is thought to drive enhanced DNA repair and treatment resistance. While chromosomal instability associated with DDR defects drives tumorigenesis, the need to preserve genomic stability to maintain fitness fosters addiction to redundant pathways promoting fork integrity. Targeting these pathways is a promising anti-cancer strategy currently undergoing clinical evaluation. In this review, we provide a molecular overview of RS and the RSR. We also explore the sources of RS in gliomas, along with the biological processes and tumor-specific features that influence the RSR in GBM cells. We then delve into the strategies developed to exploit RS, including strategies harnessing the DDR to foster antitumor immunity.