Antigen-Presenting Cancer-Associated Fibroblasts Modulate Tumor Microimmunity

Abstract

Cancer-associated fibroblasts (CAFs) are key regulators of tumor progression, immune modulation, and therapeutic resistance within the tumor microenvironment. Advances in single-cell and spatial profiling have revealed substantial heterogeneity among CAF populations, challenging the traditional view of CAFs as a uniformly tumor-promoting stromal population. Among the identified fibroblast states, antigen-presenting CAFs (apCAFs) represent a distinct subset characterized by major histocompatibility complex class II expression and the ability to directly interact with cluster of differentiation (CD) 4+ T cells. First described in pancreatic ductal adenocarcinoma, apCAFs have since been observed in multiple tumor types. Unlike professional antigen-presenting cells, apCAFs lack classical costimulatory molecules, suggesting that their antigen presentation leads to non-canonical immune outcomes, including immune modulation, immune tolerance, or regulatory T cell induction. Recent evidence indicates that apCAFs arise from multiple cellular sources, most prominently mesothelial cells undergoing mesothelial-to-mesenchymal transition in response to tumor-derived signals such as interleukin-1 and transforming growth factor-β. Additional studies have identified fibrocyte-like apCAFs derived from bone marrow–derived cells, underscoring the heterogeneous and context-dependent nature of this fibroblast state. Consistent with their antigen-presenting capacity, apCAFs localize to immune-enriched niches, including tertiary lymphoid structures, where they influence local immune architecture and T cell functional states. Notably, apCAFs have been linked to both tumor-promoting and tumor-restraining activities, highlighting their dual roles in cancer immunity. Importantly, these immunological functions have direct clinical implications: apCAF-enriched stromal programs are associated with distinct immune landscapes and may influence responses to immune checkpoint blockade. This review summarizes current knowledge of the biology of apCAFs, with emphasis on their defining molecular features, cellular origins, immunological functions, and clinical relevance. Therefore, defining the context-dependent roles of apCAFs will be essential for designing next-generation stromal-targeted and immunotherapy-combination strategies that selectively enhance antitumor immunity while limiting tumor-promoting fibroblast functions.