Ciclopirox reprograms effector responses and modulates Notch1 activation in activated human T cells

Summary Ciclopirox (CPX) is an FDA approved, broad-spectrum antifungal agent. The prodrug of CPX, fosciclopirox, was evaluated for safety and preliminary efficacy in patients with advanced solid tumors, including bladder cancer, and was found to inhibit cell proliferation, the γ-secretase complex, and Notch signaling. However, the effects of CPX on human T cell function have remained undefined. In this study, we investigated the impact of CPX on primary human T cell activation and their effector responses. CPX enhanced early activation markers and IL-2 production; yet, suppressed activation-driven expansion, altered cell cycle progression, and reduced effector functions, including IFN-γ production and cytotoxic granule expression, in vitro. Mechanistically, CPX modulates Notch1 activation temporally and reprograms T cell metabolism by limiting glycolysis, both of which impact proliferative and effector responses in activated T cells. Together, these findings identify CPX as a modulator of T cell immunity, highlighting the broader immunologic implications for its therapeutic application.