# Replication Stress in Cancer: Mechanistic Insights and Therapeutic Opportunities for Radiosensitization

## TL;DR

This paper explores how replication stress in cancer cells can be targeted to improve cancer treatment by making tumors more sensitive to radiation.

## Contribution

The paper provides a comprehensive review of replication stress mechanisms and novel therapeutic strategies for radiosensitization.

## Key findings

- Cancer cells rely on replication stress response mechanisms, making them vulnerable to targeted disruption.
- Targeting proteins like ATR, Chk1, and PARP shows promise in preclinical and clinical studies for radiosensitization.
- Replication stress links to immune activation via the cGAS–STING pathway, offering new therapeutic insights.

## Abstract

Replication stress (RS) is a hallmark of cancer, largely driven by oncogene activation. Due to high levels of RS, cancer cells depend heavily on the RS response mechanisms to avoid DNA damage. This dependency creates a therapeutic opportunity that can be exploited for more effective cancer treatment. This review synthesizes current mechanistic understanding of RS and RS response and further describes how targeted disruption of RS response proteins (ATR, Chk1, Wee1, PARP, RPA) has been used in preclinical and clinical studies. We summarize preclinical and emerging clinical evidence for exploiting RS for radiosensitization, and outline candidate biomarkers and functional assays for patient selection. We also highlight the links between RS, therapy-induced senescence and innate immune activation via the cGAS–STING (cyclic GMP-AMP synthase—Stimulator of Interferon Genes) pathway, and address current challenges and future directions.