T-cell mesenchymal transition represents a potential pathogenic mechanism of female cancer-related lymphedema

Cancer-related lymphedema (CRL), the most common type of secondary lymphedema, seriously reduces the life quality of cancer patients. In-depth studies on the pathogenesis of CRL are limited, impeding the development of therapeutic approaches. In this study, an analysis of intercellular heterogeneity reveals a trend towards fibrosis in skin cell subpopulations and identifies the phenomenon of T-cell mesenchymal transition (TcMT). T cells with a mesenchymal phenotype—fibroblast-like (Fib-like) T cells and myofibroblast-like (Myofibro-like) T cells—exhibit a unique fibrotic phenotype and impaired immune function. Furthermore, PDGFRB expression by Fib-like T cells in the affected skin is likely to influence disease severity by regulating TcMT. Additionally, we observe the manifestation of the fibrotic phenotype of T cells in single-cell data from the stromal vascular fraction (SVF) of CRL patients, suggesting that TcMT may be a pathological feature and potential therapeutic target of CRL and providing deep insights into disease pathophysiology. The unclear pathogenesis of cancer-related lymphedema (CRL) impedes therapeutic development. The authors here identify T-cell mesenchymal transition (TcMT) in CRL, where T cells acquire a fibrotic phenotype, offering a potential therapeutic target.