Mapping the Immune Landscape of Systemic Sclerosis: From Cellular Crosstalk to Precision Therapeutic Strategies The Immune Landscape of Systemic Sclerosis: From Pathogenic Mechanisms to Precision Therapeutic Breakthroughs

Mengguo Liu^*

• Huashan Hospital, Fudan University, Shanghai, China

Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by immune dysregulation, microvascular damage, and multi-organ fibrosis. Recent breakthroughs in single-cell and spatial multi-omics technologies have profoundly revealed the high heterogeneity of the SSc immune microenvironment, including extensive aberrant activation of innate immunity (e.g., dendritic cells, macrophages, neutrophils) and adaptive immunity (T cells, B cells), and their interaction with fibroblasts and endothelial cells through an "immune-stromal-vascular" network that collectively drives the fibrotic process. These findings have advanced disease subtyping based on molecular features (e.g., inflammatory, fibrotic) and the development of precision therapeutic strategies. Emerging therapies targeting the IL-6 receptor (tocilizumab), B cells (rituximab, CAR-T), the JAK-STAT pathway (tofacitinib, baricitinib), and T-cell co-stimulation (abatacept) have shown potential to improve disease progression in clinical studies. However, heterogeneity in treatment response, difficulty in reversing fibrosis, and the lack of biomarkers remain current challenges. Future efforts require integrating multi-omics and artificial intelligence technologies to build dynamic predictive models, promoting multi-target combination and individualized therapies, ultimately aiming for early intervention and long-term remission in SSc. Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by immune dysregulation, microvascular damage, and multi-organ fibrosis. Recent breakthroughs in single-cell and spatial multi-omics technologies have profoundly revealed the high heterogeneity of the SSc immune microenvironment, including extensive aberrant activation of innate immunity (e.g., dendritic cells, macrophages, neutrophils) and adaptive immunity (T cells, B cells), and their interaction with fibroblasts and endothelial cells through an "immune-stromal-vascular" network that collectively drives the fibrotic process. These findings have advanced disease subtyping based on molecular features (e.g., inflammatory, fibrotic) and the development of precision therapeutic strategies. Emerging therapies targeting the IL-6 receptor (tocilizumab), B cells (rituximab, belimumab,CAR-T), the JAK-STAT pathway (tofacitinib, baricitinib), and T-cell co-stimulation (abatacept) have shown potential to improve disease progression in clinical studies. However, heterogeneity in treatment response, difficulty in reversing fibrosis, and the lack of biomarkers remain current challenges. Future efforts require integrating multi-omics and artificial intelligence technologies to build dynamic predictive models, promoting multi-target combination and individualized therapies, ultimately aiming for early intervention and long-term remission in SSc.