Ferroptosis Of Tumor Cells Research Articles

Etomoxir Sodium Salt Promotes Imidazole Ketone Erastin-Induced Myeloid-Derived Suppressor Cell Ferroptosis and Enhances Cancer Therapy.

Although ferroptosis inducers trigger ferroptotic tumor cells and immune cells in the tumor microenvironment (TME), imidazole ketone erastin (IKE)'s induction of ferroptosis shows no effect on tumor growth in immunocompetent tumor-bearing mice due to the presence of myeloid-derived suppressor cells (MDSCs). Treatment of the carnitine palmitoyltransferase 1a (CPT1A)-specific inhibitor decreases the immunosuppressive function of MDSCs and enhances ferroptotic inducer-initiated tumor cell ferroptosis. However, whether blocking CPT1A could enhance IKE-induced MDSC ferroptosis and thereby inhibit tumor growth is still unclear. Here, we report that a CPT1A-specific inhibitor, etomoxir sodium salt (Eto), and IKE combined treatment increased MDSC ferroptosis. Interestingly, the combination treatment of Eto and IKE blocked MDSCs' immunosuppressive function and accumulation by downregulating the expression of SLC7A11, GPX4, and ARG1 while promoting T-cell proliferation and infiltration into tumor tissues to enhance cancer therapy. These data provide a rationale for the combination therapy of a specific CPT1A inhibitor, Eto, with IKE in clinical settings.

EGCG-enabled Deep Tumor Penetration of Phosphatase and Acidity Dual-responsive Nanotherapeutics for Combinatory Therapy of Breast Cancer.

The presence of dense collagen fibers is a typical characteristic of triple-negative breast cancer (TNBC). Although these fibers hinder drug penetration and reduce treatment efficacy, the depletion of the collagen matrix is associated with tumor metastasis. To address this issue, epigallocatechin-3-gallate (EGCG) is first exploited for disrupting the dense collagenous stroma and alleviate fibrosis by specifically blocking the TGF-β/Smad pathway in fibroblasts and tumor cells when intraperitoneally administrated in TNBC tumor-bearing mice. A methotrexate (MTX)-loaded dual phosphate- and pH-responsive nanodrug (pHA@MOF-Au/MTX) is next engineered by integrating Fe-based metal-organic frameworks and gold nanoparticles for improved chemo/chemodynamic therapy of TNBC. Surface modification with pH (low)-insertion peptide substantially enhanced the binding of the nanodrug to 4T1 cells owing to tumor stroma remodeling by EGCG. High-concentration EGCG inhibited glutathione peroxidase by regulating mitochondrial glutamine metabolism, thus facilitating tumor cell ferroptosis. Furthermore, sequential EGCG and pHA@MOF-Au/MTX treatment showed remarkable anti-tumor effects in a mouse model of TNBC, with a tumor growth inhibition rate of 79.9%, and a pulmonary metastasis rate of 96.8%. Altogether, the combination strategy developed in this study can improve the efficacy of chemo/chemodynamic therapy in TNBC and represents an innovative application of EGCG.

Abstract A036: DDR2 in ovarian tumor CAFs controls ferroptosis and response to Olaparib

Abstract In ovarian cancer, resistance to conventional cancer treatments has stimulated finding alternative targets that induce tumor cell death. Ferroptosis, a lipid peroxide-triggered form of iron-dependent cell death, is one such pathway. Current research has focused primarily on tumor cell-intrinsic mechanisms or how tumor associated immune cells might impact tumor cell ferroptosis. Cancer-associated fibroblasts (CAFs) are other key stromal cells in the tumor microenvironment and play critical roles in cancer progression, metastasis, and chemotherapeutic response. In ovarian cancer, the collagen receptor tyrosine kinase DDR2 is predominantly expressed by tumor stromal CAFs, not immune cell, and high tumor stromal cell expression of DDR2 in ovarian tumors is associated with poor survival and resistance to therapy. Thus, we asked whether DDR2 could impact ferroptosis regulation in CAFs, and if so, how this effect of DDR2 could impact ovarian tumor cell responses to cytocidal therapies. Through various genetic means, we generated multiple DDR2-expressing and DDR2-deficient human ovarian tumor and mouse breast tumor CAFs. We evaluated the response of the various CAFs to ferroptosis inducers (Erastin and RSL3) and inhibitors (Ferrostatin-1 and Deferoxamine). We find that the presence of DDR2 in CAFs protects these cells from induced ferroptosis through regulation of the xCT- GSH-GPX4 antioxidant pathway and cellular iron metabolism. DDR2-dependent regulation of xCT-GSH-GPX4 occurs through non-canonical activation of NRF2 via the Sequestosome-1 (SQSTM1/p62) protein. In iron metabolism, DDR2 affects the labile iron pool (LIP) by regulating ferritinophagy. The actions of DDR2 in CAFs protects these cells against Olaparib therapy, by inhibiting Olaparib-induced ferroptosis. Ovarian tumor CAF culture supernatant was found to protect ovarian tumor cell response to Erastin-induced ferroptosis, in a DDR2- dependent manner. Overall, this study uncovered a novel function of the action of DDR2 in tumor stromal CAFs in controlling iron and the xCT-GSH-GPX4 ferroptosis regulatory axis through non-canonical p62-KEAP1-NRF2 activation. These findings suggest that CAFs, through DDR2-mediated regulation of ferroptosis, could play a role in therapeutic sensitivity/resistance in ovarian cancer. Citation Format: Julien Lesage, Alessandra DiMauro, Katherine C. Fuh, Gregory D. Longmore. DDR2 in ovarian tumor CAFs controls ferroptosis and response to Olaparib [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A036.

Iron-based MOF with Catalase-like activity improves the synergistic therapeutic effect of PDT/ferroptosis/starvation therapy by reversing the tumor hypoxic microenvironment

Reversing the hypoxic microenvironment of tumors is an important method to enhance the synergistic effect of tumor treatment. In this work, we developed the nanoparticles called Ce6@HGMOF, which consists of a photosensitizer (Ce6), glucose oxidase (GOX), chemotherapy drugs (HCPT) and an iron-based metal-organic framework (MOF). Ce6@HGMOF can consume glucose in tumor cells through “starvation therapy”, cut off their nutrition source, and produce gluconic acid and hydrogen peroxide (H2O2). Utilizing this feature, Ce6@HGMOF can produce oxygen through catalase-like catalytic activity, thereby reversing the hypoxic microenvironment of tumors. This strategy of changing the hypoxic environment can help to slow down the growth of tumor blood vessels and improve the drug-resistant microenvironment to some extent. Meanwhile, increasing the supply of oxygen can enhance the effect of photodynamic therapy (PDT) and enhance the oxidative stress damage caused by reactive oxygen species (ROS) in tumor cells. On the other hand, cancer cells usually produce higher levels of glutathione (GSH) to adapt to high oxidative stress and protect themselves. The Ce6@HGMOF we designed can also consume GSH and induce ferroptosis of tumor cells through Fenton reaction with H2O2, while enhancing the effect of PDT. This innovative synergistic strategy, the combination of PDT/ferroptosis /starvation therapy, can complement each other and enhance each other. It has great potential as a powerful new anti-tumor paradigm in the future.

3-Bromopyruvate modified with cholesterol enhances anti-hepatoma activity by inducing ferroptosis and apoptosis

Ferroptosis offers an alternative to traditional apoptotic pathways for cancer therapy. Efficient glycolytic pathways reduce tumor sensitivity to ferroptosis. We hypothesize that inhibiting glycolysis to enhance tumor cell ferroptosis could be a potential strategy for cancer therapy. This study aimed to synthesize a pH-responsive prodrug of 3-bromopyruvate-cholesteryl ester (3-BP-CL) to improve the specific distribution of 3-bromopyruvate (3-BP)—an efficient antitumor alkylating agent capable of selectively inhibitng hexokinase-2 (HK-2) activity—to the tumor, hence increasing its efficacy and reducing toxicity. The results showed that the prodrug could release 3-BP in an acidic environment, thus increasing reactive oxygen species (ROS) production, inhibiting glutathione peroxidase 4 expression, increasing Fe2+ and lipid peroxide levels, and finally inducing ferroptosis in hepatoma cells. In addition, 3-BP-CL increased ROS production by releasing 3-BP, further promoting the apoptosis of hepatoma cells. Cell migration, growth, and in vivo experiments revealed a significantly higher anti-hepatocellular carcinoma effect of 3-BP-CL than 3-BP in mice (P < 0.05). Unlike 3-BP, 3-BP-CL displayed no toxicity to mice. These results suggested that 3-BP-CL was a promising prodrug for hepatoma treatment and acted via ferroptosis and apoptosis pathways.

Natural diterpene carrier-free hydrogel enhances antigen presentation and intensifies T cell activation for tumor immunotherapy

Although immunotherapy has revolutionized cancer treatment, the low immunogenicity, insufficient T cells intratumoral infiltration and defective antigen presentation in the “cold” tumor microenvironment limit its clinical application. To address this challenge, enlightened by the clinical combined application of antitumor herb medicines, we developed a carrier-free hydrogel KEEM by integrating multiple natural active lipophilic components with manganese ions into a natural co-assembled ternary system. The KEEM hydrogel induced the formation of hydroxyl radicals by Fenton-like reactions, leading to apoptosis, while simultaneously inducing tumor cell ferroptosis through the system xc−-GSH-GPX4 axis. Subsequent release of damage-associated molecular patterns (DAMPs) proved the emergence of immunogenic cell death (ICD). Additionally, manganese ions could directly activate the cGAS-STING pathway, further amplifying the immunostimulatory effects. This synergistic effect promoted dendritic cell maturation thus enhancing antigen presentation, and mediating the change of tumor microenvironment (TME) from “cold” to “hot”. In hepatoma ascites and melanoma models, KEEM combined with immune checkpoint blockade and adoptive T cell therapy respectively demonstrated promising anti-tumor effects in vivo, meanwhile showing excellent biocompatibility and biosafety. Thus, the combination of this multi-diterpenoids carrier-free hydrogel with immunotherapy offers a new strategy for clinical immune-refractory tumor treatment.

A Multifunctional Exosome with Dual Homeostasis Disruption Augments cGAS-STING-Mediated Tumor Immunotherapy by Boosting Ferroptosis.

Ferroptosis has shown great potential in activating antitumor immunity. However, the cunning tumor cells can evade ferroptosis by increasing the efflux of iron and promoting the production of the reductant glutathione to mitigate oxidative stress. Herein, a multifunctional exosome loaded with manganese-doped iron oxide nanoparticles (MnIO), GW4869, and l-buthionine sulfoximine (BSO) is developed to disrupt the iron metabolism homeostasis and redox homeostasis to enhance tumor immunotherapy. The efficient transport of MnIO by exosomes and the inhibition of iron exocytosis by GW4869 led to a high retention of up to 29.57% ID/g for iron in the tumors. Such a high retention of iron, in combination with the BSO-induced disruption of the redox homeostasis, effectively promotes the ferroptosis of tumor cells. Consequently, the multifunctional exosomes that noticeably enhance ferroptosis by dual homeostasis disruption provoke the cGAS-STING-based antitumor immune response and effectively suppress tumor growth and lung metastasis in orthotopic breast cancer.

ATP-activated Fe(Ⅲ)/carbon dots assemblies for in situ generating nanozyme and simultaneously monitoring tumor cell ferroptosis

The integration of nanomedicine and nanocatalysis has currently resulted in the emergence of synthesized nanozymes with disruptive potential in alternative cancer therapy. However, the in situ synthesis of nanozymes using an intracellular components remains a formidable challenge. In this study, the inactivated Fe(Ⅲ)/carbon dots nanoassemblies (Fe/CDs-A) were prepared through Fe3+-induced assembly of red emissive CDs. In tumor cells overexpressing adenosine triphosphate (ATP), Fe/CDs-A can be activated and disassembled, causing the specific release of CDs and simultaneous formation of Fe3+-ATP nanocomplexes in situ due to the enhanced coordination between intracellular ATP and Fe3+. Intriguingly, Fe3+-ATP nanocomplexes were found to possess peroxidase (POD)-like activity, efficiently generating highly toxic •OH in the presence of acidic H2O2 in tumor cells, thereby inducing tumor cells ferroptosis. Simultaneously, the released CDs initially penetrate the lysosomes of tumor cells and ultimately accumulate in the nuclei of dead/dying cells, achieving real-time monitoring cell death process through their recovered red emission. Overall, for the first time, the well-designed Fe/CDs-A demonstrates its capability as ATP-triggered inducers for in situ generation of nanozymes and specific release of CDs. This study offers a novel pathway for in situ generation of nanozymes for precise cancer therapy.

4-Methyl-N-(Piperidin-1-Ylmethylene) Benzenesulfonamide (PMSA) Promotes Ferroptosis of Tumor Cells by Targeting the KEAP1-NRF2-GPX4 Axis.

We aimed to investigate the effect of 4-methyl-N-(piperidin-1-ylmethylene) benzenesulfonamide (PMSA) on tumor cell proliferation, migration, ferroptosis, and the potential molecular mechanism of ferroptosis in tumor cells. PMSA was produced in the marine biomedical research institute of Guangdong Medical University (Zhanjiang, China) and used for tumor cells treatment. MTT and cell colony formation assays were used to measure the inhibition of tumor cell proliferation, the scratch assay was used to identified the suppression of tumor cell migration, the death of tumor cells was measured by Annexin-V-FITC/PI staining, the level of ferroptosis-relative lipid ROS in tumor cells was measured by flow cytometry and MDA detection kit, and the expression of ferroptosis-relative protein was measured by Western blot. The Discovery Studio system was used for molecular docking and the binding ability was measured by cellular thermal shift assay. The PMSA we produced inhibited tumor cell proliferation, colony formation, migration and triggered cell death, and Fer-1 could reverse these effects. The amount of ROS and MDA levels in tumor cells was also markedly raised by PMSA. PMSA treatment significantly reduced the expression of SLC7A11/XCT, NRF2, and GPX4 in tumor cells. The phosphorylation level of NRF2 was also decreased. Through molecular docking, it was discovered that PMSA could bind to NRF2 and thereby block its activity. The KEAP1-NRF2-GPX4 axis was the target of PMSA's anti-tumor action, which results in ferroptosis of tumor cells. This demonstrated that the compound has the potential to be used as a candidate for anti-tumor drugs.

The arylbipyridine platinum (II) complex increases the level of ROS and induces lipid peroxidation in glioblastoma cells.

Here we present the biological properties of the arylbipyridine platinum (II) complex (arylbipy-Pt) and describe the potential mechanism of its antitumor action which differs from that of the well-known cisplatin. Leading to the oxidative stress and lipid peroxidation, the arylbipyridine platinum (II) complex showcases the significant cytotoxicity against the glioblastoma cells as shown by the MTT test. Using the 5-ethyl-2-deoxyuridine we study the proliferative activity of glioblastoma cells to affirm that arylbipyridine platinum (II) complex does not impede cell division or DNA replication. Staining by the MitoCLox dye and 2',7'-dichlorodihydrofluorescein diacetate demonstrates that the glioblastoma cells treated with arylbipy-Pt exhibit a strong increase of the lipid peroxidation and the stimulation of the reactive oxygen species formation. The hypothesis that arylbipy-Pt promotes oxidative death of tumor cells is confirmed by control experiments using N-acetyl-L-cysteine as an antioxidant. Further evidence for the oxidative mechanism of action is provided by real-time PCR, which shows high expression levels for genes associated with the heat shock proteins HSP27 and HSP70, which can be used as markers of tumor cell ferroptosis. To elucidate the chemical nature of the arylbipy-Pt complex activity, we perform 195Pt NMR spectroscopy and cyclic voltammetry measurements under biologically relevant conditions. The results obtained clearly indicate the structural transformation of the arylbipy-Pt complex in the DMSO-saline mixture, which is crucial for its further antitumor activity via the oxidative pathway. The found correlation between the molecular structure of arylbipy-Pt and its effect on the tumor cell cycle paves the way for the rational design of Pt complexes possessing the alternative mechanism of antitumor activity as compared to DNA intercalation, providing possible solutions to the major problems such as toxicity and drug resistance.

Coating Dormant Collagenase-Producing Bacteria with Metal-Anesthetic Networks for Precision Tumor Therapy.

Tumor malignancy highly depends on the stiffness of tumor matrix, which mainly consists of collagen. Despite the destruction of tumor matrix is conducive to tumor therapy, it causes the risk of tumor metastasis. Here, metal-anesthetic network-coated dormant collagenase-producing Clostridium is constructed to simultaneously destruct tumor matrix and inhibit tumor metastasis. By metal-phenolic complexation and π-π stacking interactions, a Fe3+-propofol network is formed on bacterial surface. Coated dormant Clostridium can selectively germinate and rapidly proliferate in tumor sites due to the ability of carried Fe3+ ions to promote bacterial multiplication. Intratumoral colonization of Clostridium produces sufficient collagenases to degrade tumor collagen mesh and the loaded propofol restrains tumor metastasis by inhibiting tumor cell migration and invasion. Meanwhile, the delivered Fe3+ ions are reduced to the Fe2+ form by intracellular glutathione, thereby inducing potent Fenton reaction to trigger lipid peroxidation and ultimate ferroptosis of tumor cells. In addition to a satisfactory safety, a single intratumoral injection of coated dormant Clostridium not only effectively retards the growth of established large primary tumors, but also significantly suppresses distal lung metastasis in two different orthotopic tumor models. This work proposes a strategy to develop advanced therapeutics for malignant tumor treatment and metastasis prevention.

Photoferroptosis as a potent strategy for neuroblastoma treatment

Photodynamic therapy (PDT) and photothermal therapy (PTT) have been developed to treat tumors with potential of clinical applications due to their high spatiotemporal selectivity and non-invasiveness. Nevertheless, the hypoxia within the tumor microenvironment (TME) limits the efficacy of PDT. PTT has the risk of damaging surrounding normal tissues due to the high temperatures essential for killing tumor cells. Herein, we propose a new tumor treatment strategy based on photo-triggered ferroptosis of tumor cells, which is termed photoferroptosis therapy (PFT). The PFT agent (CuS&AIPH@PEG-PAE@PM) was synthesized by encapsulating a radical generator (2,2’-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride, AIPH) and a photothermal agent (copper sulfide, CuS) into an amphiphilic polymer (poly(ethylene glycol)-poly(β-amino ester), PEG-PAE) via self-assembly and a following coating with platelet membrane (PM). Under near-infrared (NIR) irradiation, the PFT agent CuS&AIPH@PEG-PAE@PM generates abundant alkyl radicals (R●) to trigger tumor cell ferroptosis in a moderate temperature and oxygen-independent manner. Meanwhile, the PFT agent also reduces the GSH level and thus suppresses GPX4 expression to promote ferroptosis, which further consolidates the antitumor effect of PFT. The PFT is expected to establish a promising phototherapy strategy against tumors, which has the potential to overcome the limitations of PDT and PTT.

NFS1 inhibits ferroptosis in gastric cancer by regulating the STAT3 pathway.

Cysteine desulfurase (NFS1) is highly expressed in a variety of tumors, which is closely related to ferroptosis of tumor cells and affects prognosis. The relationship between NFS1 and the development of gastric cancer (GC) remains unknown. Here we showed that NFS1 expression was significantly higher in GC tissues compared to adjacent normal tissues. Patients with high expression of NFS1 in GC tissues had a lower overall survival rate than those with low expression. NFS1 was highly expressed in cultured GC cells compared to normal gastric cells. Knockdown of NFS1 expression reduced the viability, migration and invasion of GC cells. In cultured GC cells, NFS1 deficiency promoted ferroptosis. Mechanistically, NFS1 inhibited ferroptosis by upregulating the signal transduction and activator of transcription 3 (STAT3) signaling pathway in cultured GC cells. NFS1 knockdown using siRNA inhibited the STAT3 pathway, reduced the expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), and elevated intracellular levels of reactive oxygen species (ROS), ferrous ion (Fe2+), and malondialdehyde (MDA) in cultured GC cells. A specific STAT3 activator significantly reversed the inhibitory effect of NFS1 deficiency on ferroptosis in cultured GC cells. These in vitro results were further confirmed by experiments in vivo using a mouse xenograft tumor model. Collectively, THESE RESULTS INDICATE THAT NFS1 is overexpressed in human GC tissues and correlated with prognosis. NFS1 inhibits ferroptosis by activating the STAT3 pathway in GC cells. These results suggest that NFS1 may be a potential prognostic biomarker and therapeutic target to treat GC.

Ferroptosis-inducing nanomedicine and targeted short peptide for synergistic treatment of hepatocellular carcinoma

The poor prognosis of hepatocellular carcinoma (HCC) is still an urgent challenge to be solved worldwide. Hence, assembling drugs and targeted short peptides together to construct a novel medicine delivery strategy is crucial for targeted and synergy therapy of HCC. Herein, a high-efficiency nanomedicine delivery strategy has been constructed by combining graphdiyne oxide (GDYO) as a drug-loaded platform, specific peptide (SP94-PEG) as a spear to target HCC cells, sorafenib, doxorubicin-Fe2+ (DOX-Fe2+), and siRNA (SLC7A11-i) as weapons to exert a three-path synergistic attack against HCC cells. In this work, SP94-PEG and GDYO form nanosheets with HCC-targeting properties, the chemotherapeutic drug DOX linked to ferrous ions increases the free iron pool in HCC cells and synergizes with sorafenib to induce cell ferroptosis. As a key gene of ferroptosis, interference with the expression of SLC7A11 makes the ferroptosis effect in HCC cells easier, stronger, and more durable. Through gene interference, drug synergy, and short peptide targeting, the toxic side effects of chemotherapy drugs are reduced. The multifunctional nanomedicine GDYO@SP94/DOX-Fe2+/sorafenib/SLC7A11-i (MNMG) possesses the advantages of strong targeting, good stability, the ability to continuously induce tumor cell ferroptosis and has potential clinical application value, which is different from traditional drugs.

A Bimetallic Nanomodulator to Reverse Immunosuppression via Sonodynamic-Ferroptosis and Lactate Metabolism Modulation.

Triple-negative breast cancer (TNBC) responds poorly to immunotherapy due to insufficient immunogenicity and highly immunosuppressive tumor microenvironment (TME). Herein, an intelligent calcium/cobalt-based nanomodulator (Ca,Co)CO3-LND-TCPP@F127-TA (abbreviated as CCLT@FT) is developed to act as a sonodynamic-ferroptosis inducer and metabolic immunoadjuvant to enhance anti-tumor immunotherapy. More details, simultaneous reactive oxygen species (ROS) generation and glutathione (GSH) depletion can be achieved due to the existence of Co2+/Co3+ redox couple in CCLT@FT. Meanwhile, mitochondrial Ca2+ overload and tetrakis(4-carboxyphenyl) porphyrin (TCPP)-mediated sonodynamic therapy (SDT) further amplify the oxidative stress and promote ferroptosis in tumor cells. More impressively, CCLT@FT can modulate lactate metabolism by doping with cobalt and loading with lonidamine (LND, an inhibitor of MCT4), thereby reversing the high-lactate immunosuppressive TME. Furthermore, the combination with immune checkpoint blockade (ICB) therapy is found to achieve superior anti-tumor immunity, which in turn promotes ferroptosis of tumor cells by downregulating SLC7A11 protein, ultimately creating a "cycle" therapy. Overall, this work demonstrates a novel strategy for enhancing anti-tumor immunotherapy based on a closed-loop enhancement therapeutic route between CCLT@FT inducing ferroptosis/lactate metabolism modulation and ICB therapy, providing an alternative and important reference for effective immunotherapy of TNBC.

A Photoactivated Self-Assembled Nanoreactor for Inducing Cascade-Amplified Oxidative Stress toward Type I Photodynamic Therapy in Hypoxic Tumors.

Type I photodynamic therapy (PDT) generates reactive oxygen species (ROS) through oxygen-independent photoreactions, making it a promising method for treating hypoxic tumors. However, the superoxide anion (O2∙-) generated usually exhibits a low oxidation capacity, restricting the antitumor efficacy of PDT in clinical practice. Herein, a photoactivated self-assembled nanoreactor (1-NBS@CeO2) is designed through integration of type I PDT and cerium oxide (CeO2) nanozymes for inducing cascade-amplified oxidative stress in hypoxic tumors. The nanoreactor is constructed though co-assembly of an amphiphilic peptide (1-NBS) and CeO2, giving well-dispersed spherical nanoparticles with enhanced superoxide dismutase (SOD)-like and peroxidase (POD)-like activities. Following light irradiation, 1-NBS@CeO2 undergoes type I photoreactions to generated O2∙-, which is further catalyzed by the nanoreactors, ultimately forming hypertoxic hydroxyl radical (∙OH) through cascade-amplified reactions. The PDT treatment using 1-NBS@CeO2 results in elevation of intracellular ROS and depletion of GSH content in A375 cells, thereby inducing mitochondrial dysfunction and triggering apoptosis and ferroptosis of tumor cells. Importantly, intravenous administration of 1-NBS@CeO2 alongside light irradiation showcases enhances antitumor efficacy and satisfactory biocompatibility in vivo. Together, the self-assembled nanoreactor facilitates cascade-amplified photoreactions for achieving efficacious type I PDT, which holds great promise in developing therapeutic modules towards hypoxic tumors.

Multifunctional single-component photosensitizers as metal-free ferroptosis inducers for enhanced photodynamic immunotherapy

Immunotherapy can enhance primary tumor efficacy, restrict distant growth, and combat lung metastasis. Unfortunately, it remains challenging to effectively activate the immune response. Here, tertiary butyl, methoxy, and triphenylamine (TPA) were utilized as electron donors to develop multifunctional photosensitizers (PSs). CNTPA-TPA, featuring TPA as the donor (D) and cyano as the acceptor (A), excelled in reactive oxygen species (ROS) generation due to its smaller singlet-triplet energy gap (ΔES-T) and larger spin-orbit coupling constant (SOC). Additionally, cyano groups reacted with glutamate (Glu) and glutathione (GSH), reducing intracellular GSH levels. This not only enhanced PDT efficacy but also triggered redox dyshomeostasis-mediated ferroptosis. The positive effects of photodynamic therapy (PDT) and ferroptosis promoted immunogenic cell death (ICD) and immune activation. By further combining anti-programmed cell death protein ligand-1 (anti-PD-L1) antibody, the powerful treatments of ferroptosis-assisted photodynamic immunotherapy significantly eradicated the primary tumors, inhibited the growth of distant tumors, and suppressed lung metastasis. In this study, a three-pronged approach was realized by single-component CNTPA-TPA, which simultaneously served as metal-free ferroptosis inducers, type-I photosensitizers, and immunologic adjuvants for near-infrared fluorescence imaging (NIR FLI)-guided multimodal phototheranostics of tumor. Statement of significance(1) CNTPA-TPA shared the smallest singlet-triplet energy gap and the largest spin-orbit coupling constant, which boosted intersystem crossing for efficient type-I photodynamic therapy (PDT);(2) Special reactions between cyano groups with glutamate and glutathione in mild conditions restricted the biosynthesis of intracellular GSH. GSH-depletion efficiently induced glutathione peroxidase 4 inactivation and lipid peroxide, resulting in ferroptosis of tumor cells;(3) The combination treatments of ferroptosis-assisted photodynamic immunotherapy induced by single-component CNTPA-TPA with the participation of anti-PD-L1 antibody resulted in increased T-cell infiltration and profound suppression of both primary and distant tumor growth, as well as lung metastasis.

Ferroptosis suppressor genes are highly expressed in esophageal cancer to inhibit tumor cell ferroptosis

To explore the role of ferroptosis-related genes in regulating ferroptosis of esophageal squamous cell carcinoma (ESCC). ESCC datasets GSE161533 and GSE20347 were downloaded from the Gene Expression Omnibus (GEO) to identify the differentially expressed genes (DEGs) using R software. ESCC ferroptosis-related genes obtained by intersecting the DEGs with ferroptosis-related genes from FerrDb were analyzed using GO and KEGG analyses, protein-protein interaction (PPI) network analysis, and core gene identification through Cytoscape. The identified ferroptosis suppressor genes were validated using TCGA database, and their expression levels were detected using RT-qPCR in cultured normal esophageal cells and ESCC cells. Six ferroptosis suppressor genes (RRM2, GCLC, TFRC, TXN, SLC7A11, and EZH2) were downregulated with siRNA in ESCC cells, and the changes in cell proliferation and apoptosis were assessed with CCK8 assay and flow cytometry; Western blotting was performed to examine the changes in ferroptosis progression of the cells. We identified a total of 58 ESCC ferroptosis-related genes, which involved such biological processes as glutathione transmembrane transport, iron ion transport, and apoptosis and the ferroptosis, glutathione metabolism, and antifolate resistance pathways. The PPI network included 54 nodes and 74 edges with a clustering coefficient of 0.522 and PPI enrichment P<0.001. Cytoscape identified 6 core ferroptosis suppressor genes (RRM2, TFRC, TXN, EZH2, SLC7A11, and GCLC), which were highly expressed in ESCC tissues in the TCGA dataset and in ESCC cell lines. Downregulating these genes in ESCC TE1 cells significantly inhibited cell proliferation, promoted cell apoptosis, reduced the expression levels of ferroptosis markers GPX4 and FIH1, and increased the expression of ACSL4. High expression of ferroptosis suppressor genes in ESCC may cause arrest of ferroptosis progression to facilitate tumor development, and inhibiting these genes can restore ferroptosis and promote cell apoptosis, suggesting their value as potential therapeutic targets for ESCC.

Zinc oxide nanoparticles with catalase-like nanozyme activity and near-infrared light response: A combination of effective photodynamic therapy, autophagy, ferroptosis, and antitumor immunity

We prepared biocompatible and environment-friendly zinc oxide nanoparticles (ZnO NPs) with upconversion properties and catalase-like nanozyme activity. Photodynamic therapy (PDT) application is severely limited by the poor penetration of UV–Visible light and a hypoxic tumor environment. Here, we used ZnO NPs as a carrier for the photosensitizer chlorin e6 (Ce6) to construct zinc oxide–chlorin e6 nanoparticles (ZnO-Ce6 NPs), simultaneously addressing both problems. In terms of penetration, ZnO NPs convert 808 nm near-infrared light into 401 nm visible light to excite Ce6, achieving deep-penetrating photodynamic therapy under long-wavelength light. Interestingly, the ability to emit short-wavelength light under long-wavelength light is usually observed in upconversion nanoparticles. As nanozymes, ZnO NPs can catalyze the decomposition of hydrogen peroxide in tumors, providing oxygen for photodynamic action and relieving hypoxia. The enhanced photodynamic action produces a large amount of reactive oxygen species, which overactivate autophagy and trigger immunogenic cell death (ICD), leading to antitumor immunotherapy. In addition, even in the absence of light, ZnO and ZnO-Ce6 NPs can induce ferroptosis of tumor cells and exert antitumor effects.

Identification of lncRNA-mRNA network linking ferroptosis and immune infiltration to colon adenocarcinoma suppression

BackgroundColon adenocarcinoma (COAD) is one of the most common malignant tumors. The interplay involving ferroptosis between tumor and immune cells plays a crucial in cancer progression. However, the biological basis of this interplay in COAD development remains elusive. MethodsTranscriptome data of COAD samples were obtained from The Cancer Genome Atlas and National Center for Biotechnology Information databases. Using single-sample gene set enrichment analysis, we calculated the ferroptosis score (FS) and immune cell infiltration levels for each sample, leveraging the expression levels of genes related to ferroptosis and various immune cell types. Samples with FSs greater than the 75th percentile were classified into the high-FS subgroup, while those below the 25th percentile were categorized as the low-FS subgroup. Moreover, tumor tissue samples and adjacent normal tissue samples were collected from twenty colon patients. Using real-time quantitative polymerase chain reaction, we validated the expression of certain genes in these samples. ResultsThe COAD samples with high FSs experienced favorable survival probability and heightened sensitivity to anticancer drugs, with FSs negatively associated with the pathological stages. Moreover, the up-regulated genes in high-FS subgroup exhibited enrichment in immune-related pathways, suggesting a correlation between immunity and ferroptosis. Importantly, we discovered a key lncRNA-mRNA co-expression network linking tumor cell ferroptosis and immune infiltration (e.g., neutrophil) in the progression and classification of COAD. Further analysis identified several ferroptosis-related lncRNAs (e.g., RP11-399O19.9) within this network, indicating their potential roles in COAD progression and deserving in-depth study. ConclusionsOur findings provide novel insights into the underlying biological basis, particularly involving lncRNAs, at gene expression level associated with ferroptosis in COAD and cancer therapy. Nevertheless, further analysis and validation are required to expand the findings.