JAK-STAT3-MYC axis defines pathogenic stem cell-like memory CD4+ T cells in rheumatoid arthritis.

Stem cell-like memory T (Tscm) cells are long-lived, self-renewing T cells that sustain chronic immune activation. We analyzed Tscm cells from 11 rheumatoid arthritis (RA) patients and 8 healthy controls using single-cell RNA sequencing and proteomics, comparing csDMARD-treated, tofacitinib-treated, and control groups. RA CD4+ Tscm cells exhibited a distinct signature with upregulation of STAT3 and downstream targets including MYC, PIM1, SOCS1, and SOCS3, while proteomic analysis of the bulk sorted Tscm population confirmed increased STAT3 and MYC-associated pathways in total Tscm cells. Although JAK inhibition partially attenuated this signaling, it did not fully suppress STAT3 activity. Notably, MYC target gene activity correlated with clinical disease severity. These findings indicate that elevated STAT3-MYC transcriptional signatures in RA CD4+ Tscm cells may contribute to treatment resistance and suggest MYC-driven transcriptional reprogramming as a potential therapeutic target.