Here, our data revealed that the mechanical sensor Piezo1, a signal node, responds to innate inflammatory and/or stiffness stimuli and integrates both the SIRT1-HIF1α-glycolysis metabolic signaling axis and calcium-calcineurin-NFAT signaling in DCs to drive TH1 differentiation while inhibiting Treg lineage commitment in inhibiting tumor growth in the context of complex tumor microenvironment. Here, PIEZO1 is linked to neoplasm.