Nanoparticle mechanical properties, as critical factors in tumor targeting drug delivery, have recently been revealed to regulate cellular biological functions. While macroscopic mechanical stimuli are demonstrated to reprogram tumor-associated macrophages (TAMs), it is unclear how TAMs respond to microscopic stimuli from nanoparticles. Herein, we demonstrated that the stiff 15%NGs presented stronger interactions with integrin than the soft 2%NGs, promoting the polymerization of actin and the activation of yes-associated protein 1. Therefore, the pro-inflammatory phenotype of TAMs was enhanced and the secretion of tumor necrosis factor α was increased. In synergy with high liver enrichment, 15%NGs exhibited superior tumor suppression by reprogramming TAMs in orthotopic liver tumors. Crucially, the pro-inflammatory phenotype of macrophages reprogrammed by 15%NGs significantly induced the apoptosis of tumor cells in ex vivo hepatocellular carcinoma tissues from patients. This study proposes a mechanical signaling pathway to reprogram TAMs by manipulating nanogel stiffness and provides new insights for rational design of cancer nanomedicines.