image: Figure 1: The proposed effect of CHEK2 loss of function on cytotoxic T-cell recruitment at different organizational levels. (A) Double stranded breaks (DSB) are resolved through either homologous recombination or the non-homologous end joining pathway. In the loss of CHEK2 function scenario, the functionality of the HR pathway is reduced, and the ability to resolve double stranded breaks fully and accurately, is diminished. Subsequently, the DNA damage response pathway attempts to resolve the DSB through the NHEJ pathway, which is less accurate and leads to the accumulation of somatic mutations. (B) The accumulation of somatic mutations produces fragments of DNA that exit the nucleus through vesicles. When DNA is released from these vesicles, cGAS recognizes the presence of cytosolic DNA and activates the downstream effectors of the cGAS-STING pathway. (C) The secondary mechanism of immune cell recruitment including CD8 T cell infiltration because of CHEK2 deficiency maybe through the downstream signaling cascade leading to the production of Type I Interferon and chemotaxis inducing cytokines following cGAS-STING pathway activation.
Credit: Copyright: © 2025 Qian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
“Taken together, CHEK2 expression has the potential to predict resistance or non-response to immunotherapy.”
BUFFALO, NY – June 20, 2025 – A new review was published in Volume 16 of Oncotarget on June 10, 2025, titled “Beyond DNA damage response: Immunomodulatory attributes of CHEK2 in solid tumors.”
In this paper, led by first author Helen Qian and corresponding author Crismita Dmello from Northwestern University Feinberg School of Medicine, researchers compiled growing evidence that the CHEK2 gene, long known for its role in repairing DNA damage, may also influence how tumors respond to immunotherapy. Their analysis suggests that problems in CHEK2 function might make cancer cells more vulnerable to immune system attacks, highlighting a new opportunity to improve treatment outcomes in solid tumors.
Immune checkpoint inhibitors (ICIs) have transformed cancer treatment; however, they are effective in only a subset of patients. This review suggests that tumors with reduced CHEK2 activity may accumulate more mutations that produce signals the immune system can recognize. These signals, known as neoantigens, help immune cells identify and destroy cancer cells more effectively. The review connects this process not only to CHEK2’s established role in the DNA damage response but also to a newly proposed function in shaping the immune environment of tumors.
CHEK2 normally helps maintain genomic stability by enabling precise DNA repair. When this function is lost, cells rely on more error-prone repair methods, leading to additional mutations. These mutations can increase tumor mutational burden, which has been linked to better outcomes with immunotherapy. Beyond DNA repair, the review highlights a second mechanism: activation of the cGAS-STING pathway. This pathway detects fragments of damaged DNA and triggers inflammation that attracts immune cells to the tumor.
The authors highlight studies where CHEK2-deficient tumors responded better to PD-1 inhibitors, a common type of immune checkpoint inhibitor. In both lab models and early-stage clinical settings, CHEK2 loss was associated with increased infiltration of CD8+ T cells—immune cells essential for attacking cancer cells. In cancers such as glioblastoma and renal cell carcinoma, which are typically resistant to immunotherapy, reduced CHEK2 expression was linked with more favorable immune activity and higher expression of interferon-related genes.
The compiled evidence points to CHEK2 as a potential biomarker for identifying patients likely to respond to immunotherapy. In addition, combining CHEK2 inhibitors with existing immunotherapies may enhance anti-tumor effects, particularly in cancers with limited treatment options. The review notes that some clinical trials using the CHEK1/2 inhibitor prexasertib alongside immune checkpoint therapies have already shown promising early results.
“The initial results from this Phase I clinical trial support the immunomodulatory role of CHEK2 expression and even suggest CHEK2 potentiates immunosuppression.”
Although more research is needed to confirm these mechanisms and improve treatment approaches, this review underscores the expanding role of DNA repair genes like CHEK2—not only in maintaining genome integrity but also in helping the immune system fight cancer.
Continue reading: DOI: https://doi.org/10.18632/oncotarget.28740
Correspondence to: Crismita Dmello – crismita.dmello@northwestern.edu
Keywords: cancer, CHEK2, immune checkpoint inhibitors, immunomodulation
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Journal
Oncotarget
Method of Research
News article
Subject of Research
Cells
Article Title
Beyond DNA damage response: Immunomodulatory attributes of CHEK2 in solid tumors
Article Publication Date
10-Jun-2025
COI Statement
C.D and A.M.S are co-authors for the following patent filed by Northwestern University: Method of using checkpoint kinase 1/2 inhibitor therapy to modulate anti-tumoral response against cancer and sensitize gliomas to immunotherapy (US Patent App. 16/951,638). A.M.S. has received in-kind and or funding support for research from Agenus, BMS, and Carthera. The remaining authors declare no other competing interests.