The primary goal of treating malignant tumors is to efficiently eliminate the primary tumor and prevent metastasis and recurrence. Unfortunately, the immunosuppressive tumor microenvironment (TME) is a significant obstacle to effective oncotherapy. Herein, a therapeutic strategy based on melittin (MLT) encapsulated in hyaluronic acid-modified metal-organic frameworks (MOFs) is pioneered, focusing on the safe delivery and TME-responsive release of MLT to reshaping the immunosuppressive TME and simultaneously activating the immune system to eradicate cancerous cells. Iron-based MOFs respond to glutathione and pH, degrade within a moderately acidic TME, and achieve tumor-specific release of MLT. Additionally, the iron-mediated Fenton reaction produces reactive oxygen species that augment oxidative stress, ultimately leading to tumor-specific ferroptosis, whereas MLT-induced membrane disruption promotes immunogenic cell death to activate the immune system. In combination with the immune checkpoint inhibitor anti-PD-L1, this nanodrug elicits potent antitumor immune responses, facilitating the infiltration of effector T cells and enhancing systemic antitumor T cell immunity to suppress both primary and distant tumors. This study demonstrates the tremendous potential of nanoscale self-destructive MOFs for the targeted transport and controlled release of MLT and reveals the promoting effect of combined MLT and ferroptosis delivery on cancer immunotherapy.