Mapping Stromal Heterogeneity and Cell–Cell Communication in the Tumor Microenvironment

The field of tumor microenvironment (TME) research has undergone a transformative shift with the advent of single-cell and spatial multi-omics technologies, which are redefining our understanding of the tumor stroma as a dynamic regulatory hub. The tumor stroma is composed of diverse cell populations, including cancer-associated fibroblasts (CAFs), endothelial cells, and immune components, all contributing to cancer progression, metastasis, and therapeutic resistance. Traditional bulk profiling methods masked key cellular heterogeneities and failed to capture spatial architecture and context-dependent interactions within the TME. Recent studies leveraging single-cell transcriptomics and spatially resolved profiling have revealed unexpected levels of stromal cell diversity, unveiling distinct subtypes and their lineage trajectories. Nonetheless, key questions remain unresolved: How do CAFs differentiate into pro- or anti-tumor subpopulations? Which molecular circuits drive stromal activation? And to what extent are stromal–tumor interactions spatially governed? Filling these knowledge gaps requires integrative, multi-dimensional approaches that unify molecular signatures, spatial organization, and functional validation.This Research Topic aims to advance the molecular dissection of tumor stromal cell heterogeneity and function through the use of single-cell and spatial multi-omics technologies. The goal is to delineate stromal cell subtypes, trace their lineage origins, decode their regulatory networks, and map their physical interactions within the tumor architecture. Studies may address questions such as how stromal cell plasticity contributes to therapy resistance, what molecular pathways govern their activation states, and how cellular neighborhoods influence stromal behavior. Ultimately, this Research Topic seeks to foster discoveries that enable precise manipulation of specific functional stromal subsets, promoting the development of targeted strategies to normalize the TME and improve therapeutic efficacy.To gather further insights into stromal biology from multi-omics perspectives, we welcome articles addressing, but not limited to, the following themes: Identification and characterization of novel stromal cell subpopulations across cancer types using single-cell and spatial omics. Mapping spatial architectures and cell–cell interactions using imaging-based technologies such as spatial transcriptomics, CODEX, or MIBI-TOF. Integrative multi-omic exploration of transcriptional, epigenetic, and proteomic networks regulating stromal activation and state transitions. Functional validation of stromal mechanisms using in vitro and in vivo models, including organoids and patient-derived xenografts. Correlations between stromal subtypes or trajectories with clinical outcomes, therapy response, or resistance mechanisms. Development of novel stromal-targeted biomarkers or therapeutic strategies informed by high-resolution omic data. Topic editors: Qiong Lu, Qi Li, Yudi Xu, CIRO ISIDORO, Jim Boyne Source: https://www.frontiersin.org/research-topics/85424/mapping-stromal-heterogeneity-and-cell-cell-communication-in-the-tumor-microenvironment