Targeting WEE1 in tumor-associated dendritic cells potentiates antitumor immunity via the cGAS/STING pathway.

DNA damage profoundly affects cancer progression and immune cell function. While research primarily focuses on tumor cells, the effects of DNA damage on immune cells remain understudied. Here, we observe significant DNA damage in tumor-associated dendritic cells (TADCs), accompanied by the upregulation of the serine/threonine kinase WEE1, a crucial regulator of DNA damage repair. Interestingly, DNA damage also stimulates DC activation. WEE1 inhibition activates TADCs through the cGAS/STING pathway, increasing IL-12 and type I interferon expression, thus enhancing the antitumor immune response and improving tumor control. Additionally, WEE1 inhibition augments the efficacy of DC vaccines and synergizes with immune checkpoint blockade therapy. These findings highlight a pivotal role of WEE1 signaling in DNA damage repair in DCs within the tumor microenvironment, which in turn suppresses the antitumor immune response. Therefore, targeting WEE1 in DCs represents a promising approach to enhance T cell activation and improve the effectiveness of cancer immunotherapy.