A Deep-Red-Absorbing Osmium(II)-Based Photosensitizer Evokes Pyroptosis by Targeting Glutamine Metabolism and Impairing Cell Redox Homeostasis

Pyroptosis plays an emerging role in cancer immunotherapy, however, most currently known compounds that activate this cell death mechanism were discovered serendipitously. Here, we report a pyroptosis-inducing strategy that works through metabolic reprogramming of cancer cells to enhance antitumor immunity. Specifically, an osmium-based photosensitizer (Os) was covalently attached to a small-molecule glutamine carrier protein inhibitor (IMD-0354), to construct the conjugate Os-IMD. This conjugate significantly enhanced the photosensitizer’s uptake into cancer cells via the glutamine metabolic pathway, inhibited glutamine uptake, and promoted mitochondrial targeting. As a result, upon light irradiation, Os-IMD induced mitochondrial damage and impaired electron transport chain function as well as intracellular redox homeostasis, leading to a switch in the mode of cell death from the apoptosis typically observed with Os to gasdermin D (GSDMD)-mediated pyroptosis. Our study offers a new avenue for the development of scalable pyroptosis-inducing agents.