Matthew S. Levine

Chemoimmunotherapy, particularly strategies that induce a tumor specific antitumor immune response, has emerged as a promising approach to improved cancer treatment. Nonetheless, only a limited number of drugs can successfully stimulate an antitumor immune response in vivo. Recent studies have highlighted the potential of metal-based anticancer agents in chemoimmunotherapy. Herein, we report a half-sandwich osmium(II) complex, Os-1, which acts as a catalyst for H2O2 generation through autocatalytic hydride transfer from coenzyme NADH to oxygen. Sustained H2O2 self-supply generation disrupts tumor redox homeostasis and induces DNA damage, leading to the activation of the cGAS-STING signaling pathway. Os-1 demonstrates potent cytotoxicity in vitro and elicits a robust antitumor immune response in vivo. Furthermore, Os-1 exhibits a synergistic antitumor growth effect when combined with a PD-1 inhibitor. To the best of our knowledge, this study is the first to describe the rational design of a small-molecule metal catalyst that provides for the in situ generation of H2O2 in cancer cells, thus overcoming the exogenous-additive bottleneck of oxidative therapy. This self-sufficient system not only promotes oxidative damage but also activates the cGAS-STING pathway, thereby integrating synergistically oxidative and immunotherapeutic actions.

A next-generation Pt( iv )–Au( i ) multimetal complex incorporating gemcitabine enhances cytotoxicity and ICD. RNA-seq pathway analysis reveals transcriptomic signatures predictive of ICD potential (created in BioRender, T. Babu).

The terms “π-stacking” and “π–π stacking” are widely used to describe attractive interactions between aromatic molecules, yet they are often interpreted as implying a distinct, π-orbital-based attractive force and a preference for a perfectly face-centered stacking geometry. Over the last three decades, structural and theoretical studies have shown that neutral, closed-shell aromatic systems instead favor T-shaped and parallel-displaced geometries and that their interaction energies can be rationalized entirely in terms of the same noncovalent forces that govern molecular interactions in general. In typical ground-state aromatic complexes, there is negligible π-orbital mixing and no demonstrable additional attractive force that is unique to π electrons. Consequently, the mechanistic content of the terms “π-stacking” and “π–π stacking” is, in most cases, ill-defined and potentially misleading when interpreted as describing a special class of interactions. Here, we advocate replacing such usage with a description in terms of Electrostatic, Dispersion, Desolvation, Induction, and Exchange-repulsion contributions (EDDIE). We further discuss those specific situations─such as charge-transfer absorptions, excitonically coupled H- and J-aggregates, and true charge-transfer salts─in which π-orbital mixing is appreciable and terminology invoking “π-stacked” systems remains physically meaningful, though still not required to describe the underlying binding forces.

Chemoimmunotherapy, particularly strategies that induce immunogenic cell death, has emerged as a promising approach to improved cancer treatment. Nonetheless, only a limited number of drugs can successfully stimulate an antitumor immune response in vivo. Recent studies have highlighted the potential of metal-based anticancer agents in chemoimmunotherapy. Herein, we report a novel piano-stool arene ruthenium(II) complex, Ru-4, which acts as a dual catalytic inhibitor of topoisomerase I and II. This inhibition induces DNA damage and activates the cGAS-STING signaling pathway, leading to the production of type I interferon and chemokines CCL5 and CXCL10. Ru-4 demonstrates potent cytotoxicity in vitro and elicits a robust antitumor immune response in vivo. Furthermore, Ru-4 exhibits a synergistic antitumor growth effect when combined with a PD-1 inhibitor. To the best of our knowledge, this study is the first to demonstrate how rationally designed ruthenium(II) complexes can promote a chemoimmunotherapeutic response via the activation of the cGAS-STING pathway through the dual catalytic inhibition of topoisomerases. It is thus expected to pave the way for the development of new chemoimmunotherapy strategies.

Viral mimicry may be an underappreciated contributor to chemotherapeutic potency in animal models and patients. This hypothesis is based on studies of a bis-Au(I)-NHC complex that was found to generate a strong anti-tumor immune response in vivo in two different challenge studies using an iKAP colorectal cancer mouse model. RNA profiling of treated cells revealed the stimulation of genes that overlap with those upregulated during a viral infection. The bis-Au(I)-NHC complex generates reactive oxygen species (ROS) through the simultaneous redox cycling of the naphthoquinone moiety and inhibition of thioredoxin reductase with Au(I). This ROS increase causes endoplasmic reticulum stress, activation of the unfolded protein response pathway and upregulation of Ifih1, a gene that encodes for the viral dsRNA sensor MDA5. Activation of MDA5 triggers a strong type I interferon response and expression of chemokine ligand 10 that can recruit immune cells to the treated tumor in a manner analogous to immune responses during viral infection. This proposed mechanism bridges the gap between cytotoxicity and the innate and adaptive immune responses. We suggest viral mimicry may be a key driver of chemotherapy potency in animals and an important determinant of positive outcomes in cancer patients.

The coordination number between the bound metal center and the supporting nitrogen atoms in single-metal-atom nitrogen-carbon catalysts (M-N-C) is an important structural parameter that can impact the catalytic activity. Understanding the structure-activity relationship between coordination number and catalytic activity is made challenging by difficulties in obtaining M-N-C catalysts with precisely controlled metal-nitrogen coordination environments. Herein, we address this challenge using heterogeneous molecular catalysts for the oxygen reduction reaction (ORR) constructed by depositing structure-defined organometallic molecules on a catalytically inert carbon nanotube substrate. The explicit metal-nitrogen coordination environments enabled us to establish accurate ORR activity-structure correlations for cobalt metal centers with first-shell Co-N coordination numbers of 3 to 5 (Co-Nx, where x = 3, 4, and 5). A good agreement between theoretical predictions and experimental ORR activity and selectivity was seen. Of note, Co atoms in an asymmetric coordination environment were found to exhibit higher activity for the two-electron (2e) ORR. Kinetic studies and operando spectroscopic measurements further revealed that the first-shell coordinating C or N atoms in asymmetric Co-N3 and Co-N5 centers could be protonated and participate in the ORR as a proton relay. The present study may aid in understanding the role of the coordination environment in other metal-based catalytic systems being applied to renewable energy conversion reactions.

Immunogenic cell death (ICD) is a form of regulated cell death capable of stimulating an adaptive immune response through release of damage‐associated molecular patterns (DAMPs). While several metal complexes have shown promise as ICD inducers, conjugates containing more than one metal center remain to be explored for ICD. Here, we report the design, synthesis, and evaluation of a tri‐metallic Au ^I ‐Pt ^IV ‐Ru ^II prodrug ( 5 ) that codelivers oxaliplatin (Type I ICD inducer), Ru ^II arene 2‐pyridinecarbothioamides (Type I), and Au(I) bis‐N‐heterocyclic (Type II) using a single scaffold. Upon reduction, complex 5 releases all three cytotoxic species, resulting in enhanced inhibition of thioredoxin reductase (TrxR1&2), elevated production of reactive oxygen species (ROS), and in vitro DAMP release. In vivo studies of complex 5 in a colorectal cancer mouse model demonstrated tumor growth suppression, reduced off‐target metal accumulation, and improved immune memory in a tumor challenge study compared to a 1:1:1 mixture of the constituent agents. Furthermore, peripheral white blood cell (WBC) profiling revealed that complex 5 activates both the innate and adaptive immune compartments. This study demonstrates an integrated chemo‐immunotherapeutic strategy that unifies multiple ICD triggers within a single prodrug framework. It thus highlights a promising approach to the creation of metal‐based multimodal anticancer therapies.

Immunogenic cell death (ICD) is a form of regulated cell death capable of stimulating an adaptive immune response through release of damage‐associated molecular patterns (DAMPs). While several metal complexes have shown promise as ICD inducers, conjugates containing more than one metal center remain to be explored for ICD. Here, we report the design, synthesis, and evaluation of a tri‐metallic Au ^I ‐Pt ^IV ‐Ru ^II prodrug ( 5 ) that codelivers oxaliplatin (Type I ICD inducer), Ru ^II arene 2‐pyridinecarbothioamides (Type I), and Au(I) bis‐N‐heterocyclic (Type II) using a single scaffold. Upon reduction, complex 5 releases all three cytotoxic species, resulting in enhanced inhibition of thioredoxin reductase (TrxR1&2), elevated production of reactive oxygen species (ROS), and in vitro DAMP release. In vivo studies of complex 5 in a colorectal cancer mouse model demonstrated tumor growth suppression, reduced off‐target metal accumulation, and improved immune memory in a tumor challenge study compared to a 1:1:1 mixture of the constituent agents. Furthermore, peripheral white blood cell (WBC) profiling revealed that complex 5 activates both the innate and adaptive immune compartments. This study demonstrates an integrated chemo‐immunotherapeutic strategy that unifies multiple ICD triggers within a single prodrug framework. It thus highlights a promising approach to the creation of metal‐based multimodal anticancer therapies.

Immunogenic cell death (ICD) is a form of regulated cell death that engages the immune system by releasing damage-associated molecular patterns, making it a promising target for cancer immunotherapy. Presented here is the synthesis and evaluation of a series of asymmetric redox-active water-soluble Au(I) bis-N-heterocyclic carbenes (Au(I) bis-NHCs). We explore the structure-activity relationships between redox activity, water solubility and ICD induction, building on our previous work with a redox-active Au(I) bis-NHC (1) that effectively induced ICD but suffered from poor water solubility. To overcome this limitation, we synthesized several water-soluble redox-active Au(I) bis-NHCs, derivatives 2-4, by modifying the imidazole moiety. Compound 2 was identified as the lead, balancing water solubility and ICD induction efficacy. This compound, featuring a naphthoquinone moiety, and was found to generate reactive oxygen species (ROS) and trigger key ICD biomarkers, including calreticulin (CRT) translocation, ATP release, and high mobility group box 1 (HMGB1) secretion. A control compound lacking the redox active naphthoquinone failed to elicit these ICD markers or promote ROS production. Across the series 1-4 a correlation was observed between ROS generation and ICD biomarker expression. In vivo studies in syngeneic immunocompetent mice demonstrated that compound 2 not only prevents CT26 colorectal cancer tumor growth upon challenge with live cancer cells but also elicits a long-lived immune response upon rechallenge 12 months later.

New glycoside-prodrugs based on the iron chelator deferasirox were designed. Selective enzymatic activation by glycosidases was observed within 24 hours, accompanied by cancer cell-selective cytotoxicity. Notably, derivative 3a, bearing a β-D-galactose moiety, showed promising selective activity against galactosidase overexpressing OvCar-3 cells (IC₅₀ 9.1 ± 1.6 μM) while maintaining low activity against fibroblast control GM5756 cells (IC₅₀ > 100 μM).