Dendritic cell Piezo1 directs the differentiation of T(H)1 and T-reg cells in cancer

Dendritic cells (DCs) play an important role in anti-tumor immunity by inducing T cell differentiation. Herein, we found that the DC mechanical sensor Piezo1 stimulated by mechanical stiffness or inflammatory signals directs the reciprocal differentiation of T(H)1 and regulatory T (T-reg) cells in cancer. Genetic deletion of Piezo1 in DCs inhibited the generation of T(H)1 cells while driving the development of T-reg cells in promoting cancer growth in mice. Mechanistically, Piezo1-deficient DCs regulated the secretion of the polarizing cytokines TGF beta 1 and IL-12, leading to increased TGF beta R2-p-Smad3 activity and decreased IL-12R beta 2-p-STAT4 activity while inducing the reciprocal differentiation of T-reg and T(H)1 cells. In addition, Piezo1 integrated the SIRT1-hypoxia-inducible factor-1 alpha (HIF1 alpha)-dependent metabolic pathway and calcium-calcineurin-NFAT signaling pathway to orchestrate reciprocal T(H)1 and T-reg lineage commitment through DC-derived IL-12 and TGF beta 1. Our studies provide critical insight for understanding the role of the DC-based mechanical regulation of immunopathology in directing T cell lineage commitment in tumor microenvironments.