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Boronic acid (or ester) is a well-known temporary masking group for developing anticancer prodrugs responsive to tumoral reactive oxygen species (ROS), but their clinic application is largely hampered by the low activation efficiency. Herein, we report a robust photoactivation approach that can spatiotemporally convert boronic acid-caged iridium(III) complex IrBA into bioactive IrNH 2 under hypoxic tumor microenvironments. Mechanistic studies show that the phenyl boronic acid moiety in IrBA is in equilibrium with phenyl boronate anion that can be photo-oxidized to generate phenyl radical, a highly reactive species that is capable of rapidly capturing O 2 at extremely low concentrations (down to 0.02%). As a result, while IrBA could hardly be activated by intrinsic ROS in cancer cells, upon light irradiation, the prodrug is efficiently converted into IrNH 2 even in limited O 2 supply, along with direct damage to mitochondrial DNA and potent antitumor activities in hypoxic 2D monolayer cells, 3D tumor spheroids, and mice bearing tumor xenografts. Of note, the photoactivation approach could be extended to intermolecular photocatalytic activation by external photosensitizers with red absorption and to activate prodrugs of clinic compounds, thus offering a general approach for activation of anticancer organoboron prodrugs.

Clinical chemotherapeutic drugs have occasionally been observed to induce antitumor immune responses beyond the direct cytotoxicity. Such effects are coined as immunogenic cell death (ICD), representing a "second hit" from the host immune system to tumor cells. Although chemo-immunotherapy is highly promising, ICD inducers remain sparse with vague drug-target mechanisms. Here, we report an endoplasmic reticulum stress-inducing cyclometalated Ir(III)-bisNHC complex ( 1a ) as a new ICD inducer, and based on this compound, a clickable photoaffinity probe was designed for target identification, which unveiled the engagement of the master regulator protein BiP (binding immunoglobulin protein)/GRP78 of the unfolded protein response pathway. This has been confirmed by a series of cellular and biochemical studies including fluorescence microscopy, cellular thermal shift assay, enzymatic assays, and so forth, showing the capability of 1a for BiP destabilization. Notably, besides 1a , the previously reported ICD inducers including KP1339, mitoxantrone, and oxaliplatin were also found to engage BiP interaction, suggesting the important role of BiP in eliciting anticancer immunity. We believe that the ICD-related target information in this work will help to understand the mode of action of ICD that is beneficial to designing new ICD agents with high specificity and improved efficacy.

Photodynamic therapy (PDT) is a spatiotemporally controllable, powerful approach in combating cancers but suffers from low activity under hypoxia, whereas photoactivated chemotherapy (PACT) operates in an O2‐independent manner but compromises the ability to harness O2 for potent photosensitization. Herein we report that cyclometalated gold(III)‐alkyne complexes display a PDT‐to‐PACT evolving photoactivity for efficient cancer treatment. On the one hand, the gold(III) complexes can act as dual photosensitizers and substrates, leading to conditional PDT activity in oxygenated condition that progresses to highly efficient PACT (ϕ up to 0.63) when O2 is depleted in solution and under cellular environment. On the other hand, the conditional PDT‐to‐PACT reactivity can be triggered by external photosensitizers in a similar manner in vitro and in vivo, giving additional tumor‐selectivity and/or deep tissue penetration by red‐light irradiation that leads to robust anticancer efficacy. [ABSTRACT FROM AUTHOR]