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

Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV⁺ OPC) is driven by viral E6 and E7 oncoproteins, which disrupt G1 checkpoint control and impose selective dependency on WEE1-mediated G2/M regulation. While this vulnerability confers sensitivity to WEE1 inhibition, its immunologic consequences remain poorly defined, and the challenge of eliciting antitumor immunity without compromising immune fitness has limited clinical translation. 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 azenosertib (ZN-c3) mediates tumor control through both 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. Instead, tumor cell-intrinsic cGAS drives immune activation through STING-competent host cells within the tumor microenvironment, revealing a non-cell-autonomous relay that circumvents viral immune evasion. Intermittent WEE1 inhibition preserves T cell fitness while maintaining antitumor efficacy, and mice achieving complete responses develop immunologic memory capable of rejecting tumor rechallenge. These findings establish intermittent WEE1 inhibition as an immune-permissive therapeutic strategy that enables antigen-specific T cell responses in HPV-driven malignancies and provides a mechanistic rationale for combination with immunotherapy.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-03-12
DOI
https://doi.org/10.64898/2026.03.10.710574
Primary Topic
interferon and immune responses
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Beatriz M. Carreno, Joseph N. Patria, Devraj Basu, Jherek Swanger et al.
bioRxiv (Cold Spring Harbor Laboratory)
interferon and immune responses
article

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

Beatriz M. Carreno, Joseph N. Patria, Devraj Basu, Jherek Swanger, Malay K. Sannigrahi, Jessica Cramer, Yasser Hussaini, Bruce E. Clurman, Sophie L. Gray-Gaillard, McGarry Houghton, Regina Stoltz, Meijie Pan, K. Rajasekaran, Jeff Kwak, Ryan M. Carey, Simone L. Park, Robert M. Brody, Gerald P. Linette, Kun Liu, Ying Liu, Gregory Steven Weinstein, Ahmed Diab, Zhiheng Zhang, Mark M. Painter, Lovely Rahgav, E. John Wherry, Justine Shamber, Yanshan Tao
article en

Abstract

Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV⁺ OPC) is driven by viral E6 and E7 oncoproteins, which disrupt G1 checkpoint control and impose selective dependency on WEE1-mediated G2/M regulation. While this vulnerability confers sensitivity to WEE1 inhibition, its immunologic consequences remain poorly defined, and the challenge of eliciting antitumor immunity without compromising immune fitness has limited clinical translation. 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 azenosertib (ZN-c3) mediates tumor control through both 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. Instead, tumor cell-intrinsic cGAS drives immune activation through STING-competent host cells within the tumor microenvironment, revealing a non-cell-autonomous relay that circumvents viral immune evasion. Intermittent WEE1 inhibition preserves T cell fitness while maintaining antitumor efficacy, and mice achieving complete responses develop immunologic memory capable of rejecting tumor rechallenge. These findings establish intermittent WEE1 inhibition as an immune-permissive therapeutic strategy that enables antigen-specific T cell responses in HPV-driven malignancies and provides a mechanistic rationale for combination with immunotherapy.

bioRxiv (Cold Spring Harbor Laboratory)
Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA), University of Washington (US), Fred Hutch Cancer Center (US), Translational Therapeutics (United States) (US), Penn Center for AIDS Research (US), UPMC Hillman Cancer Center (US), Institute of Immunology (HR), Drexel University (US), University of Pennsylvania (US)
American Association for Cancer Research, Fred Hutchinson Cancer Research Center, University of Pennsylvania, University of Washington, Max-Planck-Institut für Chemie, National Institutes of Health, Perelman School of Medicine, University of Pennsylvania, Stand Up To Cancer
Good health and well-being
Openalex Percentile: Top 25%
interferon and immune responses
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