Silencing HPV: the rise of RNA therapeutics in cervical cancer

Despite the availability of preventative HPV vaccinations, cervical cancer remains a worldwide health concern. It is mostly caused by persistent infection with high-risk human papillomaviruses. Therapeutic techniques targeting the viral oncogenes E6 and E7, which are constitutively expressed in HPV-positive cervical cancers and inactivate the important tumor suppressors, p53 and Rb, offer intriguing molecular treatment options. RNA-based techniques, such as tiny interfering RNA, short hairpin RNA, antisense oligonucleotides, and mRNA-based vaccines for the selective silencing of E6/E7 genes, have emerged as leaders in targeted therapeutics. Preclinical studies have shown that RNA-mediated suppression of E6/E7 can restore p53 and Rb activity, causing apoptosis or senescence in cervical cancer cells and inhibiting tumor growth in animal models. Similarly, mRNA vaccination platforms encoding E6/E7 have been found to potently induce HPV T-cell responses and full tumor regression in animal models. RNA-based therapeutics in patients are now being evaluated in early-stage clinical studies, including novel mRNA vaccines for HPV-positive malignancies in combination with immunotherapies. While no RNA-based treatment for cervical cancer has yet achieved regulatory approval, this review summarizes the significant progress in this field that has been effective in therapies for cervical cancer using new strategies, such as advanced delivery systems, combinatorial treatments, and genome editing strategies.