CHK1 inhibition increases the therapeutic response to radiotherapy via antitumor immunity in ARID1A-deficient colorectal cancer.

Colorectal cancer (CRC) ranks among the most commonly diagnosed cancers globally and is characterized by high mortality rates and significant intertumoral heterogeneity driven by somatic mutations and an immunosuppressive tumor microenvironment (TME). Despite the success of immune checkpoint blockers (ICBs) in various malignancies, the immunosuppressive TME limits their therapeutic efficacy in the majority of CRC patients. Therefore, strategies to unleash antitumor immunity are imperative to increase the therapeutic outcomes of these patients. ARID1A mutation is frequently observed in cancers and is known to be associated with tumor activity and poor prognosis, such as colorectal cancer. Additionally, ARID1A deficiency is associated with a reduced mismatch repair capacity, increased cancer mutability, and increased infiltration of immune cells, thus potentiating the efficacy of ICBs. In this study, we revealed that ARID1A regulates CHK1 protein stability through DDB1-mediated ubiquitination. ARID1A deficiency results in CHK1 upregulation and cytosolic single-strand DNA (ssDNA) accumulation. Targeting the ATR/CHK1 axis triggers cancer cell-intrinsic innate immunity via the STING-mediated DNA-sensing pathway, thereby enhancing the therapeutic efficacy of radiotherapy (RT) and ICBs in ARID1A-deficient tumors. Taken together, these findings suggest that targeting the CHK1 checkpoint may serve as a therapeutic strategy to remodel the TME and enhance the response to radiotherapy and ICBs in ARID1A-deficient CRC.