Fibroblasts and immunocytes interact in fibrosis, playing critical roles in tissue repair, fibrosis, and cancer immune evasion. This review summarizes the molecular mechanisms and clinical trials targeting fibroblast-immunocyte interactions in fibrosis. Fibroblasts, once considered neutral, are now recognized as key immune sentinel cells that regulate immune responses. They interact with immunocytes through paracrine signals, ECM remodeling, and direct modulation, contributing to fibrosis progression. The study highlights the importance of understanding these interactions for developing effective therapies. Fibroblasts exhibit heterogeneity across organs, with distinct gene expression patterns. The crosstalk between fibroblasts and immunocytes is essential for tissue homeostasis and disease progression. In fibrosis, immune cells such as macrophages, T cells, and Tregs interact with fibroblasts, influencing fibrosis outcomes. For example, M2 macrophages promote fibroblast activation, while Th1 cells inhibit it. Tregs can both promote and suppress fibrosis depending on the context. In pulmonary fibrosis, TGF-β, IL-13, and IL-17 are key mediators. In liver fibrosis, macrophages and HSCs contribute to fibrosis through cytokine secretion. Cardiac fibrosis involves myofibroblasts and macrophages, while kidney fibrosis is driven by fibroblasts and macrophages. Clinical trials targeting fibroblast-immunocyte interactions include PDGF inhibitors, galectin-3 inhibitors, and FGF inhibitors. These therapies aim to reduce fibrosis by modulating fibroblast and immunocyte interactions. The review emphasizes the need for further research to develop targeted therapies for fibrosis.Fibroblasts and immunocytes interact in fibrosis, playing critical roles in tissue repair, fibrosis, and cancer immune evasion. This review summarizes the molecular mechanisms and clinical trials targeting fibroblast-immunocyte interactions in fibrosis. Fibroblasts, once considered neutral, are now recognized as key immune sentinel cells that regulate immune responses. They interact with immunocytes through paracrine signals, ECM remodeling, and direct modulation, contributing to fibrosis progression. The study highlights the importance of understanding these interactions for developing effective therapies. Fibroblasts exhibit heterogeneity across organs, with distinct gene expression patterns. The crosstalk between fibroblasts and immunocytes is essential for tissue homeostasis and disease progression. In fibrosis, immune cells such as macrophages, T cells, and Tregs interact with fibroblasts, influencing fibrosis outcomes. For example, M2 macrophages promote fibroblast activation, while Th1 cells inhibit it. Tregs can both promote and suppress fibrosis depending on the context. In pulmonary fibrosis, TGF-β, IL-13, and IL-17 are key mediators. In liver fibrosis, macrophages and HSCs contribute to fibrosis through cytokine secretion. Cardiac fibrosis involves myofibroblasts and macrophages, while kidney fibrosis is driven by fibroblasts and macrophages. Clinical trials targeting fibroblast-immunocyte interactions include PDGF inhibitors, galectin-3 inhibitors, and FGF inhibitors. These therapies aim to reduce fibrosis by modulating fibroblast and immunocyte interactions. The review emphasizes the need for further research to develop targeted therapies for fibrosis.