Oligomycin A Induces Apoptosis‐to‐Pyroptosis Switch against Melanoma with Sensitized Immunotherapy

Abstract Induction of mitochondrial‐targeted therapies is demonstrated to be predominantly effective in malignant melanoma therapeutics mediated by programmed cell death (PCD). The pivotal control to switch cell apoptosis to pyroptosis is exhibited to overcome the apoptosis‐resisting characters and induce immune responses against the melanoma. Yet approaches to trigger this switch are limited by far. In the present work, it is found that oligomycin A (OA), a mitochondrial respiratory inhibitor, can effectively suppress mitochondrial functionalities and induce the intracellular oxidative stresses in situ, ultimately inducing apoptosis‐to‐pyroptosis switch against melanoma. The authors have encapsulated OA into the designed cyclic argine‐glycine‐aspartic (c(RGDyC)) decorated iron constructed metal‐organic framework (MIL101‐NH 2 ‐Fe) to develop tumorous glutathione responsive nanocatalytic therapeutics, aiming to trigger intensive apoptosis‐to‐pyroptosis PCD against melanoma, accompanied with the sensitized immunotherapy via the immune checkpoint blockade. The present work offers a prominent PCD switch to destruct melanoma with promising clinical perspectives.