Cellular plasticity and heterogeneity underlying therapy resistance in 3D cervical cancer models.

Abstract

Despite the success of prophylactic vaccination and screening programs, cervical cancer remains a major cause of cancer-related morbidity and mortality worldwide, particularly in low- and middle-income countries. In cervical cancer, therapeutic resistance cannot be explained by viral status alone and instead reflects broader tissue level and microenvironmental determinants. Increasing clinical and experimental evidence indicates that these processes are driven by dynamic cellular plasticity and microenvironmental adaptation rather than fixed genetic alterations alone. Three-dimensional (3D) model systems, including multicellular spheroids and patient-derived organoids, have transformed the study of cervical cancer by preserving tissue architecture, epithelial hierarchy, and spatial gradients of oxygen, nutrients, and signaling cues that are lost in conventional two-dimensional cultures. These models reveal how hypoxia, metabolic reprogramming, extracellular matrix interactions, and immune modulation converge to promote reversible, stress-tolerant cell states with stem-like features. In particular, 3D systems uncover hypoxia-associated redox adaptation, enhanced DNA damage repair capacity, and sustained viral oncogene expression within spatially defined niches that exhibit reduced sensitivity to cisplatin and radiotherapy. Here, we synthesize current advances in 3D cervical cancer modeling to illustrate how these platforms enable direct observation of resistance mechanisms that remain inaccessible in 2D systems. We discuss how organoids and advanced 3D culture systems provide mechanistic insight into plasticity programs operating in HPV-associated cervical cancer, tumor microenvironment remodeling, and the emergence of therapy-resistant states, while offering improved translational relevance for drug testing. Collectively, this review positions 3D cell culture models as a key tool for dissecting the dynamic biology of cervical cancer resistance and for guiding the rational design of therapeutic strategies aimed at preventing relapse.