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. Author manuscript; available in PMC: 2024 May 29.
Published in final edited form as: Nat Rev Drug Discov. 2022 Oct 6;22(1):38–58. doi: 10.1038/s41573-022-00558-5

Fig. 6 |. Mechanism of immune response sensitization.

Fig. 6 |

Replication stress can elicit an innate immune response by releasing DNA particles into the cytoplasm, activating the cGAS–stimulator of interferon genes (STING) pathway, and upregulating the type I interferon-γ (IFNγ) response and, subsequently, the nuclear factor-κB (NF-κB) pathway. Besides this pro-inflammatory signal, cGAS–STING can also upregulate PDL1 expression. In addition, the ATR–CHK1 pathway can also lead to PDL1 protein degradation by activating the CDK1–speckle-type POZ protein (SPOP) pathway. Downregulation of PDL1 can inhibit an IFNβ-mediated pro-apoptotic pathway, resulting in autocrine cytotoxic signalling. IFNAR1, interferon-α/β receptor 1. *The resulting effect of ATR-CHK1-WEE1 inhibition on PD-L1 is disputable with studies showing both upregulation or downregulation upon blockage of the ATR-CHK1-WEE1 pathway.