Swanger, J. | Search bioRxiv

bioRxiv2026

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.

cancer biology↗

bioRxiv2021

Global and context-specific transcriptional consequences of oncogenic Fbw7 mutations

Fbw7 is a ubiquitin ligase substrate receptor that targets proteins for proteasomal degradation. Most known Fbw7 substrates are transcription factors (TFs) and many are also oncoproteins (e.g., c-Myc, c-Jun, Notch). Fbw7 is an important tumor suppressor and FBXW7 mutations drive tumorigenesis through activation of oncogenic Fbw7 substrates. Defining the mechanisms of Fbw7-associated tumorigenesis is critical for developing targeted therapies. We thus determined the transcriptional consequences of oncogenic Fbw7 mutations by studying isogenic colorectal cancer cell lines with engineered FBXW7 null and heterozygous missense mutations. We used an integrated approach employing RNA-Seq and high-resolution mapping (CUT&RUN) of histone modifications and TF occupancy (c-Jun and c-Myc) to examine the combinatorial effects of mis-regulated Fbw7 substrates. Fbw7 mutations caused widespread transcriptional changes associated with active chromatin and altered TF occupancy at distal regulatory regions. Some regulatory changes were common to both FBXW7-mutant cell lines whereas others were FBXW7 mutation-specific. By comparing c-Jun and c-Myc binding sites, we also identified co-regulated elements, suggesting that Fbw7 substrates may have synergistic effects. One co-regulated gene was CIITA, a master regulator of MHC Class II gene expression, and Fbw7 loss increased CIITA and MHC Class II gene expression in colorectal cancer cells. Fbw7 mutations were also correlated with increased CIITA expression in TCGA colorectal tumors and cell lines, which may have immunologic implications for progression and treatment of Fbw7-associated cancers. This integrative analysis provides a framework for understanding normal and neoplastic context-specific Fbw7 functions.

cancer biology↗