Spatial ecotype in tumor immune exclusion: from spatial architecture to therapeutic strategies

Abstract

The tumor microenvironment (TME) exhibits widespread immunophenotypic heterogeneity. Based on the spatial immune contexture, tumor immune profiles can be classified as immune-inflamed, excluded, or desert. Immune-excluded tumors, a distinct tumor immune phenotype, are characterized by the presence of immune cells (especially CD8 + T cells) near tumors but a lack of direct physical contact between immune and tumor cells. Accumulating evidence indicates that tumor immune exclusion is a spatially organized and actively maintained microenvironmental state associated with poor prognosis, impaired T cell infiltration, and resistance to immunotherapy. However, the biological mechanisms and spatial profiling underlying this phenotype remain unclear. Advances in spatial omics technologies and analytical tools have enabled the dissection of the complex spatial architecture of immune-excluded tumors. In this review, we describe recent insights into the core cellular subsets and spatial interaction networks of immune-excluded tumors, incorporating the spatial immune contexture, to provide new theoretical foundations and intervention strategies targeting spatial ecotypes to enhance T cell infiltration and sensitize immune-excluded tumors to immunotherapy. Collectively, these findings support a shift from cell-centric models towards ecotype-centered frameworks in which spatially coordinated cellular alliances govern immune accessibility and therapeutic response. Furthermore, we discuss current challenges in this field, including standardization of spatial multi-omics data integration, real-time monitoring of dynamic spatiotemporal evolution, and optimization of clinical translation pathways. Future investigations should incorporate long-term sampling, organoid models, and basket trial designs to enable precise immune-intervention strategies based on spatial ecotypes.