Cytokine context shapes antigen-presenting and matrix-producing states of cancer-associated fibroblasts

Cancer-associated fibroblasts (CAFs) exhibit remarkable functional heterogeneity, with conserved subtypes observed across diverse malignancies. However, their shared roles in shaping the tumor microenvironment (TME) and their dynamic plasticity remain incompletely understood. In this study, through integrated single-cell and spatial transcriptomic profiling across four cancer types, we identified two distinct immunomodulatory CAF states, termed antigen-presenting CAFs (apCAFs) and matrix-producing CAFs (mCAFs). Across multiple solid tumors, apCAFs were associated with enhanced anti-tumor immune features and favorable prognosis, whereas mCAFs were associated with immunosuppressive characteristics and poorer clinical outcomes. Spatial analyses revealed distinct localization patterns of apCAFs and mCAFs within the TME. Functionally, patient-derived apCAFs promoted T-cell migration, proliferation, and activation, whereas mCAFs suppressed these responses in vitro. Pan-cancer analyses further revealed a strong inverse correlation between apCAF and mCAF abundance across tumor tissues. Mechanistically, IFN-γ and TGF-β-associated signaling contexts were linked to distinct CAF transcriptional programs, with IFN-γ promoting apCAF-associated features and TGF-β favoring mCAF-associated features, suggesting a potential role of cytokine context in shaping CAF state heterogeneity. Clinically, apCAFs correlated with favorable immunotherapy response, whereas mCAFs predicted poor therapeutic outcomes. Collectively, these findings identify conserved immunomodulatory CAF subtypes across cancers, reveal distinct cytokine-associated CAF programs, and support stromal reprogramming as a promising strategy to enhance immunotherapy efficacy.