HPV-associated Anal Dysplasia in Solid Organ Transplant Recipients: A Transplant-specific Model of Mucosal Immune Dysfunction

ABSTRACT: Solid organ transplant recipients face an increased risk of human papillomavirus (HPV)-associated anal cancer because of chronic immunosuppression and impaired viral control. The natural history and underlying biology of anal dysplasia in this population remain poorly defined, and current management is largely extrapolated from human immunodeficiency virus-associated disease. Transplant-related immune dysfunction differs fundamentally from other immunocompromised states, with direct effects on T-cell activation, antigen presentation, and immune memory that are central to HPV control. In this overview, we integrate insights from HPV-driven carcinogenesis, HIV-associated anal disease, and transplant immunology to propose a transplant-specific framework of mucosal immune dysfunction. In this model, HPV immune evasion synergizes chronic immunosuppression to impair antiviral cellular immunity, promoting persistent infection, and a protumorigenic microenvironment characterized by T-cell dysfunction, impaired antigen presentation, regulatory immune polarization, and metabolic reprogramming. These processes are hypothesized to facilitate progression to high-grade squamous intraepithelial lesions, the immediate precursor to anal cancer. This framework provides a biologic basis to interpret clinically observed persistence and recurrence of anal dysplasia in solid organ transplant recipients, highlights key knowledge gaps and may inform transplant-specific screening, therapeutic strategies, and prospective studies in this high-risk population.