These findings reveal that the regulation of Tfh by MSC-Exos in this study is not confined to a single target but involves simultaneous network regulation of Stim1–Orai1–NFAT/NF-κB axis and MCU-dependent mitochondrial calcium overload, resulting in potent inhibition of Tfh in SLE. Here, STIM1 is linked to systemic lupus erythematosus.