Mechanical force receptor Piezo1 regulates T_H9 cell differentiation

Interleukin (IL)-9-producing CD4⁺ T cells (T_H9) are essential for mediating antitumor immunity, but the mechanisms of T_H9 cell differentiation remain unclear. Here, we found that the mechanical force receptor Piezo1 is critical for regulating T_H9 cell differentiation. Piezo1 deficiency in CD4⁺ T cells intrinsically inhibited T_H9 cell differentiation, whereas ectopic Piezo1 expression promoted this process. Notably, Piezo1 deficiency inhibited T_H9 cell differentiation and contributed to tumor development. Mechanistically, Piezo1 deficiency inhibits T_H9 cell differentiation mainly through the SIRT3-succinate dehydrogenase A (SDHA)-oxidative phosphorylation (OXPHOS) pathway. SIRT3 deficiency or blockade of SDHA-OXPHOS signaling activity reversed the T_H9 cell differentiation induced by Piezo1 deficiency. Moreover, HIF1α signaling is responsible for the T_H9 cell differentiation induced by Piezo1 deficiency. Thus, our findings identify a redox metabolism signaling mechanism regulated by the mechanical force receptor Piezo1 that limits the mitochondrial SIRT3-SDHA-dependent OXPHOS pathway and triggers HIF1α-IL-9 to reprogram T_H9 cell differentiation, with implications for future immunotherapy approaches.