人乳头瘤病毒阳性（HPV+）口咽鳞状细胞癌（OPSCC）的患病率迅速增加，超过宫颈癌成为发达国家最常见的HPV相关癌。由于患者对标准激烈治疗非常积极反应，重点已经转向降低治疗强度。然而，最近多中心临床试验未能在整体人群中显示减低强度治疗的非劣性，凸显了选择可能对减轻强化治疗有反应的低风险患者的需求。相反，有相当比例的患者在激励疗法后发生复发疾病。这表明HPV+OPSCC不是一个均质的疾病，而是由临床和生物变异组成的不同亚型。该综述的总体目标是鉴定与HPV+OPSCC相关的生物标记物，可能对个体化治疗中的患者分层具有意义。我们从多方面的角度讨论HPV+OPSCC的异质性，包括临床行为、肿瘤形态和分子表型。讨论了大块肿瘤和单细胞测序数据的分子分析作为肿瘤亚组间异质性的潜在驱动因素。最后，我们评估可能妨碍对HPV+OPSCC异质性进行深入研究的关键挑战，并概述潜在的未来方向，包括关于种族和民族差异的部分。 © 2023. 作者。

The incidence of human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is rising rapidly and has exceeded cervical cancer to become the most common HPV-induced cancer in developed countries. Since patients with HPV + OPSCC respond very favorably to standard aggressive treatment, the emphasis has changed to reducing treatment intensity. However, recent multi-center clinical trials failed to show non-inferiority of de-escalation strategies on a population basis, highlighting the need to select low-risk patients likely to respond to de-intensified treatments. In contrast, there is a substantial proportion of patients who develop recurrent disease despite aggressive therapy. This supports that HPV + OPSCC is not a homogeneous disease, but comprises distinct subtypes with clinical and biological variations. The overall goal for this review is to identify biomarkers for HPV + OPSCC that may be relevant for patient stratification for personalized treatment. We discuss HPV + OPSCC as a heterogeneous disease from multifaceted perspectives including clinical behavior, tumor morphology, and molecular phenotype. Molecular profiling from bulk tumors as well as single-cell sequencing data are discussed as potential driving factors of heterogeneity between tumor subgroups. Finally, we evaluate key challenges that may impede in-depth investigations of HPV + OPSCC heterogeneity and outline potential future directions, including a section on racial and ethnic differences.© 2023. The Author(s).