Hafsa Iqbal, Waad H Abuwatfa
Over 660,000 women develop cervical cancer annually, caused by persistent infection with high-risk human papillomavirus (HPV). Published studies of mesenchymal stem/stromal cells (MSCs) as immunomodulatory agents are contradictory, with some reporting tumor suppression and others tumor promotion. The mechanism of these paradoxes has not been systematically investigated. This review aims to assess MSC-mediated immune evasion in HPV-related cervical cancer, quantify HPV stratification failure in the literature, and formulate a predictive stratification model linking MSC behavior to HPV oncogenic activity. A systematic review was performed following PRISMA 2020 guidelines across 8 databases. Studies were included if they reported an MSC intervention for cervical cancer with one or more immune-related outcomes. HPV stratification gap analysis was performed alongside data extraction and risk-of-bias evaluation. 14 studies were included: 13 completed preclinical and 1 ongoing clinical trial. MSC effects included immune evasion through adenosine, IL-10, and M2 macrophage polarization, and tumor suppression through STAT3, Wnt/β-Catenin, and epigenetic pathways. Of 13 completed studies, none measured HPV oncogenic activity as an experimental variable. Only two included an HPV-negative cohort. Differential effects of MSC exosomes on HPV16 and HPV18 cell lines were recorded but not linked to HPV genotype. HPV oncogenic activity is an unmeasured and plausible modifier of MSC activity in cervical cancer. Stratification by HPV oncogenic status should be a methodological requirement for interpretable and translatable evidence, because E6/E7 signalling is linked to PDL-1, TGF-β, STAT-3 and NF-κB, all linked to MSC immunomodulatory pathways. A predictive stratification system and minimum reporting standards are suggested.