Tumor microenvironment dynamics in gastric cancer pathogenesis and therapeutic resistance

Gastric cancer remains a significant global health challenge due to its high incidence and mortality, and limited treatment options in advanced stages. Notably, gastric cancer exhibits a complex tumor microenvironment (TME) with substantial cellular and spatial heterogeneity, which profoundly impacts disease pathogenesis and therapeutic resistance. Genetic mutations and chronic inflammation contribute to its development by promoting abnormal cell proliferation and creating an immunosuppressive TME. The TME comprises various cellular and acellular components—including tumor-infiltrating lymphocytes, myeloid lineage cells such as tumor-associated macrophages and myeloid-derived suppressor cells, cancer-associated fibroblasts, extracellular matrix, and peripheral nerves—that interact with cancer cells, influencing tumor initiation, progression, immune evasion, and resistance to therapy. These elements modulate immune responses, remodel the extracellular matrix, and facilitate tumor growth and metastasis, thereby adding to the complexity of the TME. Moreover, the TME plays a critical role in therapeutic resistance through mechanisms involving angiogenesis, fibrosis, and metabolic reprogramming. Understanding the dynamic interactions within the TME offers opportunities to develop novel therapeutic strategies. Emerging approaches targeting the TME—including modulation of immune components, inhibition of fibrosis, normalization of angiogenesis, and disruption of metabolic pathways—hold promise in overcoming therapeutic resistance. Advances in technologies such as single-cell sequencing and spatial transcriptomics further enhance our understanding of TME heterogeneity, paving the way for personalized medicine in gastric cancer treatment. This review summarized the current knowledge of the cellular and molecular composition of the TME of gastric cancer, its role in disease pathogenesis and therapy resistance, and explores potential therapeutic strategies targeting TME components.