Structural cell communities in the tumor microenvironment: Spatial determinants of therapeutic response

Despite advances in cancer therapies, treatment responses remain highly variable due to the complexity and heterogeneity of the tumor microenvironment. The tumor microenvironment comprises malignant, immune, stromal, and endothelial cells, along with extracellular matrix and soluble factors, all organized into spatially distinct communities that evolve dynamically throughout tumor progression and therapy. These spatial structures orchestrate tumor behavior, immune evasion, and drug resistance. Recent breakthroughs in spatial omics technologies, including spatial transcriptomics and spatial proteomics, have enabled high-resolution, multiplexed mapping of tissue architecture and molecular characteristics. These technologies provide valuable insights into how the spatial organization of cells and signaling networks within the tumor microenvironment influences therapeutic efficacy. Notably, specific structures, such as tertiary lymphoid structures, fibroblast-mediated stromal barriers, and vascular heterogeneity have been identified as spatial determinants of treatment response. By delineating cellular communities and their interactions, spatial omics technologies can reduce intratumoral complexity into clinically interpretable modules. This review summarizes the diversity of these spatial structures and their relationships with treatment outcomes in immunotherapy, chemotherapy, radiotherapy, and targeted therapy. In addition, it highlights present challenges in data integration, analytical standardization, and functional validation, and discusses future directions for incorporating spatial omics technologies into precision medicine.