ArticleTranslational oncology2026
The SMAC-mimetic xevinapant differentially enhances cisplatin and immune checkpoint blockade efficacy in high-risk HPV-positive tumors.
Article in Translational oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
objectivesHPV-positive and HPV-negative head and neck squamous cell carcinomas (HNSCC) represent biologically distinct disease entities with divergent molecular and clinical features. Although inhibitors of apoptosis protein (IAP) antagonists have demonstrated radiosensitizing activity, recent phase III trials, including TrilynX, underscore the need for biologically informed patient selection and rational combination strategies. This study aimed to define context-dependent vulnerabilities of HPV-positive HNSCC to the SMAC mimetic xevinapant independent of radiotherapy. MATERIALS AND
methodsHPV-positive and HPV-negative human HNSCC cell lines were assessed for sensitivity to xevinapant alone or combined with cisplatin using clonogenic survival, apoptosis assays, western blotting, and DNA damage analyses. Transcriptomic profiling was performed to identify treatment-associated signaling programs. In vivo efficacy was evaluated using orthotopic xenograft models treated with xevinapant and cisplatin. Immunomodulatory effects were examined in immunocompetent syngeneic mouse models expressing HPV16 E6/E7 following treatment with xevinapant and anti-PD-1 antibody.
resultsHPV-positive HNSCC models exhibited greater sensitivity to xevinapant monotherapy than HPV-negative counterparts, associated with rapid cIAP1 degradation, enhanced apoptosis, and disruption of the HPV E7-Rb-E2F axis. Xevinapant synergized with cisplatin, augmenting DNA damage and apoptotic signaling in vitro. Combination therapy suppressed tumor growth and prolonged survival in orthotopic xenografts without overt toxicity. In syngeneic models, IAP inhibition enhanced anti-PD-1 efficacy and suppressed tumor progression. Transcriptomic analyses revealed activation of type I and type II interferon signaling pathways.
conclusionThese findings identify a biologically defined vulnerability of HPV-positive HNSCC to IAP blockade and support xevinapant as an apoptosis-sensitizing and immunomodulatory agent rather than a uniform therapeutic intensifier.
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