<p>Radiotherapy (RT) is a primary modality in clinical cancer treatment. However, its ability to induce tumor cell apoptosis offers limited activation of anti-tumor immunity. Pyroptosis, characterized by cell swelling, membrane rupture, and the release of pro-inflammatory cytokines, has been demonstrated to potentiate immune responses against cancer cells. Herein, we develop hollow spiky manganese oxide (HSpiM) nanocarriers to enhance RT-induced tumor pyroptosis and elicit anti-tumor immune responses. The spiked structure of HSpiM nanocarriers promotes intracellular lysosomal rupture, while simultaneously producing elevated amounts of reactive oxygen species (ROS) after RT, to synergistically activate the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome. Notably, lysosomal rupture-induced autophagy inhibition amplifies NLRP3-mediated pyroptosis by blocking lysosome-mediated degradation pathways. Moreover, we encapsulate an ESCRT inhibitor, the Ca²⁺ chelator BAPTA-AM, into HSpiM nanocarriers (designated as BA@HSpiM) to promote tumor pyroptosis by disrupting the repair of damaged cell membranes. RT-induced pyroptosis elicits potent anti-tumor immunity, effectively suppressing tumor metastasis and generating durable immune memory to reject tumor rechallenge. Overall, inducing tumor pyroptosis presents a promising strategy to enhance the efficacy of RT, as it improves the outcomes of local treatment and activates systemic anti-tumor immune responses.</p> Graphical Abstract <p></p>