Programmable Magneto-Mechanoporation of Lysosomes Instructs Dynamic Macrophage Polarization for Antitumor Immunity

Immune cells respond to mechanical forces and alter their functions through mechanotransduction. Unfortunately, in vivo mechanical tools that can precisely tune immune responses in a remote and programmable fashion are lacking, which impedes the understanding of mechanotransduction in immunity. Here, we develop a magnetic lysosomal membrane perforation (MagLMP) strategy to dictate dynamic macrophage polarization, which temporally triggers lysosome mechanoporation and allows membrane repair via the programmed torque-induced vortex effect under the magnetic field. Intriguingly, beta-galactoside binding lectin galectin-9 is revealed to be critical for the sensing of cyclic MagLMP, which thereby dynamically activates AMP-activated protein kinase (AMPK) for sustained M1 polarization of macrophages, followed by the mounting of antitumor immunity. Together, we establish a MagLMP platform for spatiotemporally activating immune responses by targeted regulation of lysosome hemostasis and uncover the underlying mechanisms of dynamic sensing and signaling transduction, paving the way for programmable immunotherapy through organelle mechanotransduction.