Temporal and spatial molecular heterogeneity of gastric cancer: Roles of post-translational modifications

Gastric cancer (GC) is a multifactorial disease responsible for significant global mortality, with approximately 1 million deaths annually. Its progression is governed by diverse molecular mechanisms, particularly protein post-translational modifications (PTMs), which play pivotal roles in either promoting or suppressing tumorigenesis. With the advent of spatiotemporal molecular omics, increasing emphasis has been placed on elucidating the temporal and spatial heterogeneity of GC. In this review, we systematically outline the temporal heterogeneity of GC across different developmental stages, integrating underlying mechanisms such as PTMs, including lactylation, ubiquitination, SUMOylation, which are the most associated ones influencing GC's spatiotemporal heterogeneity. Furthermore, we delineate the spatial heterogeneity of GC through comparative analyses of distinct features, such as proximal versus distal GC, primary versus metastatic lesions, superficial versus deep regions within primary tumors, and gastric mucus-secreting versus non-mucus-secreting adenocarcinoma. By synthesizing key molecular mechanisms and regulatory factors, this review aims to provide valuable insights for clinical practice, facilitating the advancement of precision medicine strategies-biomarker-guided therapy selection and spatial profiling for surgery planning, etc.