Immune-skewed stromal–immune axis defined by antigen-presenting-like adipose stromal cells in lymphedema

Background Lymphedema, a chronic and progressive disease, is characterized by lymphatic dysfunction, persistent inflammation, fibrosis, and pathological adipose tissue remodeling. Although adipose-derived stromal cells (ASCs) are implicated in disease progression, the stromal cell states and stromal–immune interactions that sustain chronic fibro-inflammatory remodeling remain poorly defined. Methods Single-cell RNA sequencing was performed of the stromal vascular fraction isolated from anatomically matched human subcutaneous adipose tissues. These tissues were obtained from patients with advanced-stage lymphedema and healthy individuals to delineate disease-associated stromal heterogeneity at single-cell resolution. Results A disease-expanded ASC progenitor population (ASC_c2) that exhibits pronounced transcriptional reprogramming in lymphedema was identified. The ASC_c2 population segregated into two mutually exclusive pathological subsets: a VCAM1⁺ vascular-interacting stromal population (V-ASCs) associated with ECM remodeling and CD74⁺HLA class II–expressing subset (I-ASCs) with antigen-presentation-like features. I-ASCs displayed a robust interferon-responsive transcriptional program consistent with immune priming and preferentially expressed the CXCL14 chemokine. Ligand–receptor interaction analysis revealed biased stromal–immune interactions between I-ASCs and CD8⁺ T cells, suggesting a skewed immune microenvironment in lymphedematous adipose tissue. Conclusions Our findings suggest an immune-skewed stromal–immune axis in lymphedema, driven by immune-primed, antigen-presentation-like ASCs. The study findings suggest a cellular framework linking stromal reprogramming to chronic immune dysregulation and fibrosis in human lymphedema, offering insights into potential therapeutic targets for interrupting pathological stromal–immune crosstalk.