Background Primary cutaneous T‐cell lymphomas (CTCLs) are a heterogeneous group of T‐cell lymphomas that begin with skin manifestations. In advanced mycosis fungoides (MF), as MF reached advanced stages, the lesions disseminated beyond the skin, involving lymph nodes and blood, which further worsened the prognosis. As no reliable malignancy markers were identified, diagnostic challenges occurred and influenced prognosis. CTCL was usually indolent; however, it progressed quickly in some patients and exhibited variable therapeutic responses. Methods This study used GEO scRNA‐seq data to analyze CTCL heterogeneity. Differential expression and enrichment analyses clarified immune and drug pathways. Monocle and CytoTRACE mapped cell trajectories, while CellChat and pySCENIC revealed intercellular communication and transcriptional regulation. Results CTCL heterogeneity was uncovered by scRNA‐seq, which identified malignant subtypes driving progression. Pathway analysis connected oxidative phosphorylation, glycolysis, and pyruvate metabolism with cellular stability, while EPCs engaged TME communication via MIF signaling to advance disease. Conclusion We examined the role of C3 STMN1+ EPCs in CTCL and discovered that this EPC subtype facilitates tumor progression, immune evasion, and angiogenesis. The C3 subtype’s heightened malignancy and specific cell cycle traits are tied to DNA replication and genomic stability. Single‐cell sequencing reveals CTCL heterogeneity and underscores the potential for personalized treatment strategies. Although our study has a limited sample size, it identifies C3 STMN1+ EPCs as potential biomarkers and therapeutic targets for CTCL, necessitating further research for broader clinical validation and offering new prospects for CTCL treatment.
Yao et al. (Thu,) studied this question.