Dissecting Cancer Metabolism and Therapeutic Resistance Using In Vitro Platforms

Understanding cancer metabolism and its adaptations is critical for developing novel therapeutic strategies. In vitro models remain indispensable tools for dissecting tumor biology and testing metabolism-based therapies. Traditional 2D monolayer cultures provide controlled, cost-effective, and reproducible platforms for mechanistic studies, genetic manipulation, and high-throughput drug screening. Advances in 3D models, such as spheroids, organoids, and microfluidic tumor-on-a-chip systems, try to come closer to a natural tumor in order to recapitulate cellular heterogeneity, nutrient and oxygen gradients, and tumor-stroma interactions. These systems provide a model that allows the study of tumor metabolic plasticity, stem-like populations, and therapy resistance mechanisms, offering improved translational relevance. Comparative studies between 2D and 3D cultures reveal significant differences in metabolic flux, drug response, and adaptation to nutrient stress, underscoring the need for integrated approaches. While 2D models remain essential for scalability and early-phase drug discovery, 3D platforms can be valuable for validating metabolic vulnerabilities and therapeutic responses under (patho)physiologically relevant conditions. Together, these complementary systems pave the way for precision oncology, enabling the identification of novel targets, optimization of drug screening, and development of personalized treatment strategies.