Exosomes in HPV-associated cancers: from biomarkers to engineered therapeutics

Abstract

Simple Summary Human papillomavirus (HPV) is the leading cause of cervical cancer and a significant contributor to several other cancers, including head and neck malignancies. Recent research highlights the role of exosomes, small extracellular vesicles involved in cell communication, as potential diagnostic and therapeutic tools in HPV-associated cancers. Exosomes can carry molecular information reflective of tumor behavior and HPV status, making them ideal candidates for non-invasive liquid biopsy. Additionally, they are being investigated for their roles in vaccine delivery, immune stimulation, and overcoming treatment resistance. This review explores how exosomal content (such as miRNAs, proteins, and lncRNAs) may be used to monitor disease progression, predict therapy response, and even serve as treatment vehicles. We also discuss challenges such as lack of standardization and the need for large cohort validation, and we highlight opportunities for clinical translation in the coming years.Abstract Background/Objectives: Human papillomavirus (HPV) is the main causative agent of cervical cancer and contributes to a significant proportion of other anogenital and oropharyngeal malignancies. The need for better biomarkers and therapeutic approaches in HPV-associated cancers has drawn attention to exosomes, small extracellular vesicles known for their stability, biomolecule transport capabilities, and role in cell-to-cell communication. Methods: This review comprehensively evaluates recent literature on the diagnostic, prognostic, and therapeutic applications of small extracellular vesicles, particularly exosomes, in HPV-related cancers. It analyzes findings on exosomal nucleic acids, proteins, and long non-coding RNAs, as well as engineered exosome-based therapies. Results: Exosomal miRNAs (e.g., miR-204-5p, miR-99a-5p, miR-21), proteins (e.g., glycolytic enzymes, HSP90), and lncRNAs (e.g., HOTAIR, DLEU1) have emerged as promising biomarkers for disease detection and monitoring. Exosomal cargo actively participates in HPV-related tumor progression. For example, miRNAs such as miR-21 and miR-146a modulate immune cell polarization and inflammatory signaling, while lncRNAs like HOTAIR promote oncogenic transcriptional programs. Exosomal proteins including HSP90 and ANXA1 facilitate extracellular matrix remodeling and immune evasion, thereby influencing tumor growth and metastasis. In HPV-positive head and neck and cervical cancers, exosomal cargo reflects HPV status, tumor progression, and treatment response. Therapeutic studies demonstrate the utility of exosomes in vaccine delivery, immune modulation, and drug delivery systems, including the use of PROTACs. However, clinical translation faces barriers including isolation protocol standardization, biomarker validation, and scalable production. Conclusions: Exosomes hold great promise for integration into diagnostic and therapeutic workflows for HPV-related cancers. Future research should focus on resolving standardization issues, validating biomarkers in diverse cohorts, and optimizing engineered exosome platforms for targeted therapy.