Deciphering immunosuppressive niches by spatial single-cell proteomics: spatial interaction networks and translational opportunities

Abstract

Although immunocheckpoint blocking therapy has been successful in a variety of cancers, its long-term response is still rare. The difference between initial clinical benefits and persistent disease control reflects the complexity of intratumor immunomodulation. People’s attention is increasingly shifting from a single group of cells to the spatial environment in which these cells live. Tumor cells, immune cells and interstitial components cannot function independently; on the contrary, they form a local tissue structure, and their composition and structure affect immune activity. Technologies such as Co-Detection by Indexing (CODEX), Imaging Mass Cytometry (IMC), and multiple ion beam imaging (MIBI) can now directly detect these spatial relationships while measuring dozens of proteins at a single cell resolution. Therefore, the spatially defined immunosuppressive niche has become an important framework for explaining how local cell interactions lead to immune dysfunction and therapeutic resistance. These studies reveal that immune cells, stromal cells, and malignant cells form a highly ordered spatial network, synergistically regulated through direct contact, cytokine signaling, and metabolic interactions. This coordinated cellular network forms a local immunosuppressive microenvironment, thereby maintaining immune escape, tumor progression, and treatment resistance. Recent research has also uncovered previously unknown immunosuppressive cell states and their spatial interaction patterns, characteristics closely related to disease prognosis, recurrence risk, and immunotherapy response. Therefore, tumor immunology research is shifting from the characterization of single cell populations to the exploration of spatially organized functional ecosystems. This article reviews the latest advances in the field of space-based single-cell proteomics and summarizes current research findings on the cellular composition, spatial structure, and regulatory mechanisms of the immunosuppressive microenvironment. Furthermore, we explore the emerging clinical value of space biomarkers and interaction networks in patient stratification, therapeutic target identification, and precision immunotherapy.