An intracellular magnetic torque-regulator drives mechano-sequential antitumor immunity

Nature creates specific structures to control mechanical plasticity for cell fate regulation. Although immune cells can sense and adapt to extracellular mechanical cues, how to activate immune responses via intracellular mechanical stimulation remains a mystery. Here, we present an intelligent intracellular magnetic torque (IIMT) paradigm that is coupled with programmed rotating magnetic fields to generate the selective mechano-stimulations in lysosomes and induce sequential antitumor immune responses. A magnetic rod-shaped micromotor (MagRM) with the a unique geometric aspect ratio is designed to exert tunable torques in antigen-presenting cells (APCs) and tumor cells. Low-intensity torque induces the mild lysosomal membrane damage to trigger antigen cross-presentation and canonical NLRP3 inflammasome activation in APCs, whereas high-intensity torque causes lysosomal membrane rupture for immunogenic cell death. In vivo studies unveil that the optimal antitumor activity is achieved by generating sequential torques from high to low intensities, which is illuminating to explore mechano-immunotherapy with selective and spatiotemporal control. Overall design: To fully explore the effects of IIMT-activated immune response in tumor microenvironment, we performed single-cell RNA sequencing (scRNA-seq) on all cells in tumors isolated at 24 h after IIMT (HL-2), MagRMs (M-1), and PBS (P-2) treatments for 10 days from the B16-OVA (BO) mice on day 11.