Cross-tissue human fibroblast atlas reveals myofibroblast subtypes with distinct roles in immune modulation

Fibroblasts, known for their functional diversity, play crucial roles in inflammation and cancer. In this study, we conduct comprehensive single-cell RNA sequencing analyses on fibroblast cells from 517 human samples, spanning 11 tissue types and diverse pathological states. We identify distinct fibroblast subpopulations with universal and tissue-specific characteristics. Pathological conditions lead to significant shifts in fibroblast compositions, including the expansion of immune-modulating fibroblasts during inflammation and tissue-remodeling myofibroblasts in cancer. Within the myofibroblast category, we identify four transcriptionally distinct subpopulations originating from different developmental origins, with LRRC15⁺ myofibroblasts displaying terminally differentiated features. Both LRRC15⁺ and MMP1⁺ myofibroblasts demonstrate pro-tumor potential that contribute to the immune-excluded and immune-suppressive tumor microenvironments (TMEs), whereas PI16⁺ fibroblasts show potential anti-tumor functions in adjacent non-cancerous regions. Fibroblast-subtype compositions define patient subtypes with distinct clinical outcomes. This study advances our understanding of fibroblast biology and suggests potential therapeutic strategies for targeting specific fibroblast subsets in cancer treatment.