Cristina Migliore, Elisabetta Fenocchio, Silvia Giordano, Simona Corso
Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide, and is associated with a very poor prognosis, largely due to its aggressive nature and, typically, late-stage diagnosis. Molecular classifications proposed one decade ago have provided valuable insights into the disease's heterogeneity and paved the way for clinical trials of tailored treatments. However, most of these trials have failed, often due to inadequate patient selection, lack of reliable biomarkers of response/resistance, or for the high level of inter- and intra-tumor heterogeneity characterizing this disease. This Review provides an in-depth and up-to-date overview of the preclinical models of GC developed in recent years. These include patient-derived xenografts (PDXs), organoids (PDOs), and genetically engineered mouse models (GEMMs), which are valuable tools for elucidating disease mechanisms and for preclinical drug testing. We also highlight emerging molecular targets and innovative therapeutic strategies-such as immunotherapies, antibody-drug conjugates, and synthetic lethality approaches-designed to overcome the mechanisms of resistance that limit current treatment efficacy. Together, these improvements offer renewed hope for more effective and durable treatment options in GC, ultimately aiming to improve patient outcomes through a more tailored approach.