An Evolutionary Research Framework for the Tumor Microenvironment in Gastric Cancer

The tumor microenvironment (TME) plays a central role in the pathogenesis, progression, and therapeutic resistance of gastric cancer (GC). Despite a rapidly expanding body of research, this field lacks a systematic conceptual framework to integrate fragmented knowledge. This study aims to construct an evolutionary framework capable of interpreting the developmental dynamics and future directions of research on the TME in GC, thereby revealing the process of its core paradigm shifts.

We conducted a systematic synthesis of the knowledge domain regarding the TME in GC and constructed a comprehensive analytical framework to trace the evolution of dominant research themes and identify associated paradigm shifts.

We propose a "two-phase evolutionary framework." Our analysis indicates that the field has transitioned from a basic mechanism exploration phase to the current translational integration phase. Early research focused on deconstructing fundamental inflammatory components, such as stromal fibroblasts and regulatory T cells, and their functions in processes like tumor growth and migration. The current paradigm has shifted decisively toward clinical translation centered on immunotherapy. This phase is characterized by concerted efforts to employ machine learning for quantifying immune infiltration, to develop prognostic models and biomarkers, and to deeply explore mechanisms of immune evasion as well as the unique TME of specific subtypes including gastroesophageal junction cancer.

This study develops an evolutionary framework for the TME in GC, charting its shift from basic research to clinical targeting. We propose that future work should focus on three connected areas: developing multi-omics integration platforms for microenvironment analysis to drive more precise prognostic and predictive models; second, exploring therapies targeting inflammatory pathways to overcome immunotherapy resistance, intensifying research on subtype-specific TME to enable personalized therapy.