Recent Advances in the Use of Osmium Complexes as Anticancer Phototherapeutics

ConspectusSince the approval of cisplatin in the late 1960s, metal-based chemotherapies have garnered a continuous amount of attention. Driven by the intrinsic limitations of platinum-based therapy, neighboring elements have been investigated for clinical use, among others, in the context of photodynamic therapy (PDT) and photoactivated chemotherapy (PACT). Ruthenium- and iridium-based photosensitizers (PSs) have led the field owing to their exceptional photophysical properties and low systemic toxicity. In contrast, osmium-based drug candidates have been slower to emerge, partly due to concerns over the well-known OsO₄ toxicity. Yet, recent developments have highlighted osmium polypyridyl complexes as promising candidates for phototherapy, thanks to their high photostability, long-lived excited states, and red-to-NIR absorption stemming from strong spin-orbit coupling. Sadler's osmium-arene complexes and McFarland's Os-4T compound, a structural analogue of the Ru-based TLD-1433 currently in clinical trial, demonstrated effective photoactivation and cytotoxicity, even under hypoxic conditions.Furthermore, osmium complexes can be chemically tuned to target organelles such as mitochondria and lysosomes or to selectively bind tumor markers such as carbonic anhydrases. Recent reports have also added an immuno-oncology dimension to osmium chemistry: the ability to trigger immunogenic cell death (ICD). This specialized cell death mode, characterized by the release of specific signaling molecules, activates dendritic cells and primes T-cell responses, converting immunologically "cold" tumors into "hot" ones. Studies from our group and others have demonstrated that photoactivated Os(II) polypyridyl complexes can efficiently induce ICD under clinically relevant red-light conditions and even in hypoxia.These features allow spatial and biochemical precision, which can also synergize with immune checkpoint inhibitors. The result is that they can function as photochemical immunoadjuvants, small molecules that combine light-induced spatial control and active targeting with the systemic reach of immunotherapy.This Account provides a timely and forward-looking overview of osmium phototherapeutics, emphasizing the link between metal-based photochemistry and cancer immunology. We contrast osmium with ruthenium, iridium, and organic systems, summarize recent in vitro and in vivo results, and propose future directions. Our laboratories have contributed several leading studies in this space, including structure-activity studies, ICD assays, and mechanistic exploration. Given the absence of a focused review in this area and the clinical momentum around both PDT/PACT and immunotherapy, the time is ideal for a concise and authoritative Account.