The Spatiotemporal Heterogeneity of Tumor-Associated Stromal Cells: Reprogramming Plasticity to Unlock Precision Cancer Immunotherapy

Tumor-associated stromal cells (TASCs) are key architects of the tumor microenvironment (TME), playing a vital role in tumor development, metastasis, and therapeutic response. Their spatiotemporal heterogeneity, characterized by dynamic phenotypic plasticity, diverse cellular subtypes, and distinct spatial distributions, offers profound insights into tumor behavior and paves the way for innovative therapy development. In particular, stromal-immune interactions reveal the powerful capacity of TASCs to shape the immune landscape, highlighting their potential as targets in immunotherapy. Despite growing evidence in functional diversity, precise mechanisms underlying the temporal evolution and spatial organization of TASCs remain elusive, impeding clinical translation. This review delved into the molecular signatures and functional states of TASCs, emphasizing their roles in tumor dynamics and therapeutic resistance. We also discussed innovative strategies targeting the plasticity of TASCs to reverse immune evasion and potentiate immune-mediated tumor eradication. Future studies should prioritize identifying spatially resolved and mechanically defined biomarkers with multi-omics and machine learning approaches, enabling a comprehensive understanding of TASCs to bridge the gap from bench to bedside.