Biological features of squamous cell carcinoma of the anus—a deep dive review

Squamous cell carcinoma of the anus (SCCA) is a human papillomavirus (HPV)-associated cancer with an increasing incidence. Localized disease is treated curatively with chemoradiotherapy (CRT) but has substantial toxicities and impact on quality of life. Despite increasing research over the past decade, much of our biological understanding of SCCA is extrapolated from other HPV-associated cancers. Recently launched initiatives aim to connect clinicians and basic researchers working in SCCA to foster collaboration and knowledge sharing and facilitate access to SCCA materials. To improve outcomes for SCCA patients, a better understanding of SCCA-specific biology is required. This review will discuss areas of SCCA biology that are important to developing targets for drug development and biomarker-based individualized precision treatment. It will discuss the current understanding of radiosensitivity, differences in HPV-positive versus HPV-negative disease, hypoxia, immune environment, molecular characteristics, circulating tumor HPV-DNA, and the microbiome. It will detail when this understanding has been extrapolated from other HPV-associated cancers. Finally, it will discuss our current and upcoming preclinical biological models and discuss future models needed to further our understanding of SCCA biology.