Minimal residual disease in cervical cancer: biological persistence, ctHPV DNA-guided surveillance, and recurrence-directed intervention

Cervical cancer remains a leading cause of cancer-related mortality among women worldwide, with approximately 30–40% of patients experiencing recurrence after definitive chemoradiotherapy for locally advanced disease. The concept of minimal residual disease (MRD)—the persistence of viable tumor clones after curative-intent treatment that escape conventional radiographic and clinical detection—has transformed surveillance and treatment paradigms in hematological malignancies and, increasingly, in solid tumors. In cervical cancer, the near-universal association with high-risk human papillomavirus (HPV) provides a unique molecular handle for MRD detection: circulating tumor HPV DNA (ctHPV DNA) released into the bloodstream by residual tumor cells. Here, we review three interconnected dimensions of MRD in cervical cancer. First, we examine the biological basis of tumor persistence after chemoradiotherapy, encompassing HPV integration-driven genomic instability, immune evasion within the irradiated tumor microenvironment, and clonal repopulation kinetics. Second, we synthesize the rapidly maturing evidence for ctHPV DNA-guided post-treatment surveillance, from digital PCR and next-generation sequencing-based detection platforms to prospective clinical validation studies demonstrating that detectable ctHPV DNA after chemoradiotherapy independently predicts recurrence with lead times of 3–6 months before radiographic progression. Third, we evaluate emerging recurrence-directed intervention strategies, including MRD-stratified treatment intensification (immune checkpoint inhibition and therapeutic HPV vaccination), adoptive cell therapy, and how integrating ctHPV DNA dynamics with immunotherapeutic approaches may define a new framework for personalized post-treatment management in this molecularly tractable malignancy.