CHK1 and CHK2 as Context-Dependent Rheostats of Genotoxic Stress: Implications for Cell Fate and Tumor Immunity.
11 affiliations
- 1Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.
- 2The Second Clinical College of China Medical University, Shenyang, 110001, China.
- 3Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, 110000, China.
- 4Health Sciences Institute, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, 110122, China.
- 5The First Clinical College of China Medical University, Shenyang, 110001, China.
- 6Shenyang City University, School of Life and Health Management, 110112, China.
- 7School of Pharmacy, Queen's University Belfast, Belfast BT7 1NN, UK.
- 8Department of Cardiology, The First Hospital of China Medical University, Shenyang, 110001, China.
- 9Department of Pathology, First Hospital of China Medical University, Shenyang, 110001, China.
- 10College of Laboratory Animal Medicine of Traditional Chinese Medicine, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, China.
- 11Clinical Translational Research Center, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110002, China.
Abstract
The DNA damage response (DDR) is a central determinant of tumor cell fate and therapeutic response. Checkpoint kinase 1 (CHK1) and checkpoint kinase 2 (CHK2) are canonical mediators of DDR, traditionally viewed as regulators of cell-cycle arrest and genome stability. Emerging evidence reveals broader roles in coordinating cell fate decisions and tumor-immune interactions. However, how checkpoint signaling translates genotoxic stress into divergent cell fate and immune outcomes remains unresolved. Here, we synthesize current evidence to propose a graded rheostat framework in which CHK1 and CHK2 integrate genotoxic stress signals to regulate diverse cell-fate and immune outputs. Although CHK1 and CHK2 share partially overlapping functions, current evidence suggests that CHK1 often contributes to stress-adaptive buffering, whereas CHK2 is more frequently implicated in damage-associated apoptotic commitment; however, these functional tendencies vary with p53 status, tumor lineage, damage characteristics including intensity and duration, treatment context, and cellular state. These distinct yet interconnected roles may be associated with emerging non-canonical programmed cell death pathways beyond canonical apoptosis, although current evidence remains limited and context-dependent. Importantly, CHK1/CHK2 signaling also shapes the tumor immune microenvironment (TIME) by regulating cytosolic DNA accumulation, cGAS-STING activation, antigen presentation, and immune checkpoint regulation. This suggests a mechanistic interface between genomic instability and anti-tumor immunity. Together, this review provides a mechanistic and translational perspective on how DDR signaling governs cell fate and immune outcomes, thereby providing a rationale for biomarker-guided combination strategies.
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BibTeX
@article{yang2026chk1,
title = {{CHK1 and CHK2 as Context-Dependent Rheostats of Genotoxic Stress: Implications for Cell Fate and Tumor Immunity.}},
author = {Jinjia Yang and Zilin Liu and Yunzhou Chen and Yanling Feng and Yilun Liu and Huiyue Zheng and Yiran Zhao and Hongbo Fang and Yuting Chen and Lin Yuan and Ming Yang and Yiming Mu and Ning Bai and Ying Zhang and Liang Wang and Xiangxuan Zhao and Liu Cao and Xiaoman Li},
journal = {International journal of biological sciences},
year = {2026},
month = sep,
doi = {10.7150/ijbs.139580},
url = {https://europepmc.org/article/MED/42910276},
note = {CC BY},
}
RIS
TY - JOUR
TI - CHK1 and CHK2 as Context-Dependent Rheostats of Genotoxic Stress: Implications for Cell Fate and Tumor Immunity.
AU - Jinjia Yang
AU - Zilin Liu
AU - Yunzhou Chen
AU - Yanling Feng
AU - Yilun Liu
AU - Huiyue Zheng
AU - Yiran Zhao
AU - Hongbo Fang
AU - Yuting Chen
AU - Lin Yuan
AU - Ming Yang
AU - Yiming Mu
AU - Ning Bai
AU - Ying Zhang
AU - Liang Wang
AU - Xiangxuan Zhao
AU - Liu Cao
AU - Xiaoman Li
PY - 2026
DA - 2026/09/24
JO - International journal of biological sciences
DO - 10.7150/ijbs.139580
UR - https://europepmc.org/article/MED/42910276
AB - The DNA damage response (DDR) is a central determinant of tumor cell fate and therapeutic response. Checkpoint kinase 1 (CHK1) and checkpoint kinase 2 (CHK2) are canonical mediators of DDR, traditionally viewed as regulators of cell-cycle arrest and genome stability. Emerging evidence reveals broader roles in coordinating cell fate decisions and tumor-immune interactions. However, how checkpoint signaling translates genotoxic stress into divergent cell fate and immune outcomes remains unresolved. Here, we synthesize current evidence to propose a graded rheostat framework in which CHK1 and CHK2 integrate genotoxic stress signals to regulate diverse cell-fate and immune outputs. Although CHK1 and CHK2 share partially overlapping functions, current evidence suggests that CHK1 often contributes to stress-adaptive buffering, whereas CHK2 is more frequently implicated in damage-associated apoptotic commitment; however, these functional tendencies vary with p53 status, tumor lineage, damage characteristics including intensity and duration, treatment context, and cellular state. These distinct yet interconnected roles may be associated with emerging non-canonical programmed cell death pathways beyond canonical apoptosis, although current evidence remains limited and context-dependent. Importantly, CHK1/CHK2 signaling also shapes the tumor immune microenvironment (TIME) by regulating cytosolic DNA accumulation, cGAS-STING activation, antigen presentation, and immune checkpoint regulation. This suggests a mechanistic interface between genomic instability and anti-tumor immunity. Together, this review provides a mechanistic and translational perspective on how DDR signaling governs cell fate and immune outcomes, thereby providing a rationale for biomarker-guided combination strategies.
SN - 1449-2288
ER -