Targeting WEE1 in tumor-associated dendritic cells potentiates antitumor immunity

DNA damage is a prevalent event within the tumor microenvironment, significantly influencing cancer initiation, progression, metastasis, and immune cell functionality. Here, we observed that oxidative stress induces DNA damage in tumor-associated dendritic cells (TADCs), leading to the activation of the serine/threonine kinase WEE1, which facilitates DNA repair. Notably, this DNA damage also acts as a stimulus for DC activation. Pharmacological inhibition of WEE1 activates TADCs via the cGAS/STING pathway, resulting in an enhanced antitumor immune response and improved tumor control. Furthermore, WEE1 inhibition augments the efficacy of DC vaccines and work synergistically with immune checkpoint blockade therapy. These findings underscore the critical role of WEE1-mediated signaling in DNA damage repair in immune cells in the tumor microenvironment, which in turn dampens the antitumor immune response. Thus, targeting WEE1 in DCs presents a promising strategy to enhance DC-mediated T cell activation and improve the effectiveness of cancer immunotherapy strategies. Overall design: Gene expression profiling analysis of RNA-seq data for bone marrow-derived dendrtic cells (BMDCs) treated with vehicle control or AZD1775.