Lipid peroxides accumulation induced ferroptosis is an effective cell death pathway for cancer therapy. However, the hypoxic condition of tumor microenvironment significantly suppresses the efficacy of ferroptosis. Here, we design a novel nanoplatform to overcome hypoxia-induced ferroptosis resistance. Specifically, we synthesized a novel kind of perfluorocarbon (PFOB) @ manganese oxide (MnOx) core-shell nanoparticles (PM-CS NPs). Owing to the good carrier of O2 as fuel, PM-CS NPs could induce higher level of ROS generation, lipid peroxidation and GSH depletion, as well as lower activity of GPX4, compared with MnOx NPs alone. Moreover, the supplement of O2 could relieve tumor hypoxia to break down the storage of intracellular lipid droplets and increase expression of ACSL4 (a symbol for ferroptosis sensitivity). Furthermore, upon stimulus of GSH or acidity, PM-CS NPs exhibit the "turn on" 19F-MRI signal and activatable T1/T2-MRI contrast for correlating with the release of Mn. Finally, PM-CS NPs exert high cancer inhibition rate for ferroptosis based therapy via synergetic combination of O2-mediated enhancement of key pathways of ferroptosis.

Overcoming Hypoxia-Induced Ferroptosis Resistance via 19F/1H-MRI Traceable Core-Shell Nanostructure.

Activation of the cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) pathway is a potent anticancer immunotherapeutic strategy, and the induction of pyroptosis is a feasible way to stimulate the anticancer immune responses. Herein, two Pt(II) complexes (Pt1 and Pt2) were designed as photoactivators of the cGAS-STING pathway. In response to light irradiation, Pt1 and Pt2 could damage mitochondrial/nuclear DNA and the nuclear envelope to activates the cGAS-STING pathway, and concurrently induce pyroptosis in cancer cells, which evoked an intense anticancer immune response in vitro and in vivo. Overall, we present the first photoactivator of the cGAS-STING pathway, which may provide an innovative design strategy for anticancer immunotherapy.

Simultaneous Photoactivation of cGAS-STING Pathway and Pyroptosis by Pt(II)-Triphenylamine Complexes for Cancer Immunotherapy.

The curative effect of sorafenib in hepatocellular carcinoma (HCC) is limited and sorafenib resistance remains a major obstacle for HCC. To overcome this obstacle, a new photoactive sorafenib-Ru(II) complex Ru-Sora has been designed. Upon irradiation (λ = 465 nm), Ru-Sora rapidly releases sorafenib and generates reactive oxygen species, which can oxidize intracellular substances such as GSH. Cellular experiments show that irradiated Ru-Sora is highly cytotoxic toward Hep-G2 cells, including sorafenib-resistant Hep-G2-SR cells. Compared to sorafenib, Ru-Sora has a significant photoactivated chemotherapeutic effect against Hep-G2-SR cancer cells and 3D Hep-G2 multicellular tumor spheroids. Furthermore, Ru-Sora inducing apoptosis and ferroptosis is proved by GSH depletion, GPX4 downregulation, and lipid peroxide accumulation. Metabolomics results suggest that Ru-Sora exerts photocytotoxicity by disrupting the purine metabolism, which is expected to inhibit tumor development. This study provides a promising strategy for enhancing chemotherapy and combating drug-resistant HCC disease.

A Photoactivated Sorafenib-Ruthenium(II) Prodrug for Resistant Hepatocellular Carcinoma Therapy through Ferroptosis and Purine Metabolism Disruption.

Perylene derivatives can be stimulated by the hypoxic tumor microenvironment to generate radical anion that is proposed to arouse electron exchange with oxidizing substance, and in turn, realize reactive oxygen species (ROS) burst. Here, three perylene therapeutic agents, PDI‐NI, PDIB‐NI, and PDIC‐NI, are developed and it is found that the minimum lowest unoccupied molecular orbital (LUMO) energy level makes PDIC‐NI most easily accept electrons from the oxidative respiratory chain to form lots of anions, and the resultant maximum ROS generation, establishing an unambiguous mechanism for the formation of perylene radical anions in the cell, presents solid evidence for LUMO energy level determining endogenous ROS burst. Stirringly, PDIC‐NI‐induced ROS generation arouses enhanced mitochondrial oxidative stress and concurrently activates immunogenic cell death (ICD), which not only efficiently kills lung tumor cells but also reprograms immunosuppressive tumor microenvironment, including the cytokine secretion, dendritic cell maturation, as well as cytotoxic T lymphocytes activation, to inhibit the growth of xenografted and metastasis tumor, presenting a proof‐of‐concept demonstration of perylene that acts as an integrated therapeutic agent to well realize hypoxia‐activated chemotherapy with ICD‐induced immunotherapy on lung cancer.

Perylene‐Mediated Electron Leakage in Respiratory Chain to Trigger Endogenous ROS Burst for Hypoxic Cancer Chemo‐Immunotherapy

Pyroptosis, as a novel mode of cell death, has been proven to have impressive antitumor effects. Dying cells undergoing pyroptosis can elicit antitumor immunity by the release of tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs). Accordingly, developing an effective, stable, and controllable nanoplatform that can promote these two side effects is a promising option for cancer therapy. In this study, we designed a carrier-free chemo-photodynamic nanoplatform (A-C/NPs) using a co-assembly strategy with cytarabine (Ara-C) and chlorin e6 (Ce6) to induce pyroptosis and a subsequent immune response against breast cancer. Mechanistically, A-C/NPs can trigger GSDME-mediated pyroptosis in a controllable manner through reactive oxygen species (ROS) accumulation, causing immunogenic cell death (ICD), in which dying cells release high-mobility group box 1 (HMGB1), adenosine triphosphate (ATP), and calcitonin (CRT). Additionally, Ara-C can stimulate the maturation of cytotoxic T lymphocytes to act synergistically with Ce6-mediated immunogenic cell death (ICD), collectively augmenting the anticancer effect of A-C/NPs. The A-C/NPs showed excellent suppressive effects on the growth of orthotopic, abscopal, and recurrent tumors in a breast cancer mouse model. The chemo-photodynamic therapy (PDT) using the proposed nanomedicine strategy could be a novel strategy for triggering pyroptosis and improving the global anticancer immune response.

Carrier-Free Nanoplatform via Evoking Pyroptosis and Immune Response against Breast Cancer.

Ferroptosis is a programmed cell death pathway discovered in recent years, and ferroptosis-inducing agents have great potential as new antitumor candidates. Here, we report a IrIII complex (Ir1) containing a ferrocene-modified diphosphine ligand that localizes in lysosomes. Under the acidic environments of lysosomes, Ir1 can effectively catalyze Fenton-like reaction, produce hydroxyl radicals, induce lipid peroxidation, down-regulate glutathione peroxidase 4, and result in ferroptosis. RNA sequencing analysis shows that Ir1 can significantly affect pathways related to ferroptosis and cancer immunity. Accordingly, Ir1 can induce immunogenic cells death and suppress tumor growth in vitro, regulate T cell activity and immune microenvironments in vivo. In conclusion, we show the potential of small molecules with ferroptosis-inducing capabilities for effective cancer immunotherapy. 

Ferroptosis‐Enhanced Cancer Immunity by a Ferrocene‐Appended Iridium(III) Diphosphine Complex

Endoplasmic reticulum (ER) degradation by autophagy (ER-phagy) is a recently revealed selective autophagy pathway that plays important roles in organelle turnover and protein degradation, but the biological functions of ER-phagy are largely unknown. Here, we present an ER-targeting Re(I) tricarbonyl complex (Re-ERLAD) that can accumulate in the ER, induce ER-to-lysosome-associated degradation (ERLAD) upon visible light irradiation, and label ER buds and track their morphological alterations during ER-phagy. The emission of Re-ERLAD is sensitive to viscosity, which is a key parameter reflecting the amount of unfolded protein in the ER. Quantitative detection using two-photon fluorescence lifetime imaging microscopy shows that ER viscosity initially increases and then decreases during ERLAD, which reveals that ERLAD is a pathway for alleviating ER stress caused by unfolded proteins. In conclusion, our work presents the first specific photoinducer and tracker of ERLAD, which can be used in studying the regulatory mechanism and function of this process. 

Real-time tracking of ER turnover during ERLAD by a rhenium complex via lifetime imaging.

Pyroptosis is a unique form of programmed cell death that is essentially proinflammatory and critical for immunity. In their Research Article(e202115800), Qian Cao, Zong-Wan Mao, and co-workers developed a carbonic anhydrase IX (CAIX)-anchored photosensitizer, CA-Re, that is capable of inducing and self-reporting membrane rupture upon irradiation, as well as evoking pyroptosis to activate antitumor immunity. CA-Re is the first metal-complex-based pyroptosis inducer, and this work provides a promising avenue for cancer metalloimmunotherapy. 

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/anie.202200692

A Carbonic Anhydrase IX (CAIX)‐Anchored Rhenium(I) Photosensitizer Evokes Pyroptosis for Enhanced Anti‐Tumor Immunity

Pyroptose ist eine einzigartige Form des programmierten Zelltods, die im Wesentlichen proinflammatorisch und entscheidend für die Immunität ist. In ihrem Forschungsartikel (e202115800) entwickelten Qian Cao, Zong-Wan Mao und Mitarbeiter einen an Carbonsäureanhydrase IX (CAIX) verankerten Photosensibilisator CA-Re, der in der Lage ist, bei Bestrahlung eine Membranruptur auszulösen und Pyroptose hervorzurufen, um Antitumorimmunität zu aktivieren. CA-Re ist der erste Pyroptose-Inducer auf der Basis eines Metallkomplexes. 

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/ange.202200692

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Papers

Ferroptosis‐Enhanced Cancer Immunity by a Ferrocene‐Appended Iridium(III) Diphosphine Complex

Real-time tracking of ER turnover during ERLAD by a rhenium complex via lifetime imaging.

Ferroptosis‐Enhanced Cancer Immunity by a Ferrocene‐Appended Iridium(III) Diphosphine Complex

A Carbonic Anhydrase IX (CAIX)‐Anchored Rhenium(I) Photosensitizer Evokes Pyroptosis for Enhanced Anti‐Tumor Immunity

A Carbonic Anhydrase IX (CAIX)‐Anchored Rhenium(I) Photosensitizer Evokes Pyroptosis for Enhanced Anti‐Tumor Immunity