New Functions of Mitochondrial Dysfunction in Gastric Cancer: From Molecular Processes to Potential Treatments

Through multifaceted reprogramming, mitochondria, the fundamental organelles of eukaryotic cells, can drive the malignant growth of malignancies. They also control energy metabolism, redox balance, and cell fate determination. Due to its high heterogeneity and primary/acquired drug resistance, gastric cancer (GC), a highly deadly and common cancer worldwide, continues to present significant clinical treatment challenges. Current targeted and immunotherapy strategies have been unable to significantly improve long-term patient survival. Thus, the pathological roles and molecular mechanisms of mitochondrial dysfunction (including mutations in mitochondrial DNA, imbalances in mitochondrial dynamics, aberrant mitophagy, abnormalities in mitochondrial permeability transition pores, and metabolic disorders) in the development of GC are systematically reviewed in this article. The specific mitochondrial phenotypic remodeling of various molecular subtypes of GC, abnormalities in membrane contact interactions between mitochondria and other organelles, the regulatory roles of mitochondrial dysfunction in tumor microenvironment (TME) immune evasion, maintenance of tumor stemness, and ferroptosis, as well as their major effects on the malignant progression and treatment resistance of GC, are all thoroughly examined. In order to provide important theoretical references and novel research perspectives for identifying therapeutic targets with greater precision, clarifying resistance mechanisms, and developing novel combination strategies in GC, this article summarizes the current research status and translational potential of anti-GC therapeutic strategies targeting mitochondria. It also explores the translational challenges currently faced in this field and the core future research directions.