Cancer-associated fibroblast heterogeneity and its role in shaping tumor immunosuppression

Cancer-associated fibroblasts (CAFs) are a dominant and functionally diverse component of the tumor stroma, long recognized for promoting tumor growth, invasion, and therapy resistance. Once viewed as a single activated cell type, CAFs are now understood to comprise multiple transcriptionally and functionally distinct subpopulations, including myofibroblastic (myCAF), inflammatory (iCAF), and antigen-presenting (apCAF) phenotypes, among others identified through single-cell and spatial transcriptomic profiling. These subsets differ substantially in their spatial localization, secretory programs, and interactions with immune cells within the tumor microenvironment. Emerging evidence indicates that specific CAF states actively contribute to immune evasion by excluding cytotoxic T cells, recruiting regulatory and myeloid-derived suppressor populations, and remodeling the extracellular matrix and metabolic conditions that constrain anti-tumor immunity. Understanding this heterogeneity is now central to explaining variable immunotherapy responses across cancer types. Despite rapid progress in characterizing CAF subtypes, key questions remain unresolved: how CAF states are induced and maintained, which subsets are causally responsible for immunosuppressive phenotypes versus merely correlated with them, and how CAF heterogeneity varies across cancer types, disease stages, and in response to therapy. This Research Topic aims to consolidate current understanding of CAF diversity and its mechanistic links to immune evasion, while highlighting recent technological advances, single-cell RNA sequencing, spatial transcriptomics, multiplexed imaging, and functional in vivo models that have enabled higher-resolution dissection of stromal-immune crosstalk. We aim to bring together studies addressing the molecular drivers of CAF subtype specification, the specific immunosuppressive mechanisms employed by distinct CAF populations (cytokine/chemokine signaling, metabolic competition, matrix remodeling, antigen presentation), and translational efforts to therapeutically target immunosuppressive CAF states to improve immunotherapy efficacy. By integrating mechanistic, computational, and clinical perspectives, this topic seeks to clarify how CAF heterogeneity can be leveraged as a biomarker and therapeutic target in the era of cancer immunotherapy.We welcome Original Research, Review, Mini Review, Case Reports and Perspective articles addressing, but not limited to:• Single-cell and spatial profiling of CAF subtypes across cancer types• Molecular and epigenetic determinants of CAF plasticity and subtype specification• Mechanisms by which specific CAF subsets suppress T cell infiltration, function, or recruit immunosuppressive myeloid/Treg populations• CAF-derived cytokines, chemokines, and metabolites shaping the immunosuppressive microenvironment• Extracellular matrix remodeling by CAFs and its impact on immune cell trafficking• Antigen-presenting CAFs and their role in modulating adaptive immunity• CAF heterogeneity as a predictive biomarker for immunotherapy response• Therapeutic strategies targeting immunosuppressive CAF subsets, alone or combined with immune checkpoint inhibitors• Computational and multi-omics approaches for resolving stromal-immune interactionsPlease note that manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this Research Topic. Topic editors: Dharambir Kashyap, PhD, Vivek Kumar Garg Source: https://www.frontiersin.org/research-topics/85090/cancer-associated-fibroblast-heterogeneity-and-its-role-in-shaping-tumor-immunosuppression