Therapeutic scheduling of WEE1 inhibition preserves T cell function and promotes immune control of HPV⁺ tumors

Human papillomavirus-associated oropharyngeal carcinoma (HPV OPC) is primarily driven by viral E6 and E7 oncoproteins, which disrupt G1 checkpoint control and impose a selective dependency on WEE1-mediated G2/M regulation. While this vulnerability confers sensitivity to WEE1 inhibition, its immunologic consequences remain poorly defined. Here, we show that WEE1 inhibition elicits durable antitumor immunity in immunocompetent models of HPV OPC. Using murine and human preclinical systems, we demonstrate that the WEE1 inhibitor ZN-c3 (azenosertib) mediates tumor control through cell-autonomous cytotoxicity and immune-dependent mechanisms requiring T cells, and conventional dendritic cells. Mechanistically, HPV tumor cells are deficient in STING signaling and fail to mount canonical type I interferon responses in vitro. Instead, tumor cell-intrinsic cGAS initiates immune activation through STING-competent host cells within the tumor microenvironment. Intermittent WEE1 inhibition preserves T cell fitness while maintaining antitumor efficacy, establishing WEE1 inhibition as an immune-enabling therapeutic strategy in HPV OPC. SignificanceWEE1 inhibition induces durable antitumor immunity against HPV oropharyngeal tumors through coordinated tumor cell-intrinsic DNA damage sensing and host STING-dependent immune activation. These findings establish intermittent WEE1 inhibition as an immune-permissive therapeutic strategy that enables antigen-specific T cell responses and provides a mechanistic foundation for rational combination with immunotherapy in HPV-driven malignancies.