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Ultrasound (US)-activated redox dyshomeostasis therapy reinforced by immunogenic cell death (ICD) through a mitochondrial targeting liposomal nanosystem.

ABSTRACT: Introduction: An imbalance in redox homeostasis consistently inhibits tumor cell proliferation and further causes tumor regression. Thus, synchronous glutaminolysis inhibition and intracellular reactive oxygen (ROS) accumulation cause severe redox dyshomeostasis, which may potentially become a new therapeutic strategy to effectively combat cancer. Methods: Mitochondrial-targeting liposomal nanoparticles (abbreviated MLipRIR NPs) are synthesized by the encapsulation of R162 (inhibitor of glutamate dehydrogenase 1 [GDH1]) and IR780 (a hydrophobic sonosensitizer) within the lipid bilayer, which are exploited for ultrasound (US)-activated tumor dyshomeostasis therapy reinforced by immunogenic cell death (ICD). Results: R162 released from MLipRIR NPs disrupts the glutaminolysis pathway in mitochondria, resulting in downregulated enzymatic activity of glutathione peroxidase (GPx). In addition, loaded IR780 can generate high levels of ROS under US irradiation, which not only interrupts mitochondrial respiration to induce apoptosis but also consumes local glutathione (GSH). GSH depletion accompanied by GPx deactivation causes severe ferroptosis of tumor cells through the accumulation of lipid peroxides. Such intracellular redox dyshomeostasis effectively triggers immunogenic cell death (ICD), which can activate antitumor immunity for the suppression of both primary and distant tumors with the aid of immune checkpoint blockade. Conclusions: Taking advantage of multimodal imaging for therapy guidance, this nanoplatform may potentiate systemic tumor eradication with high certainty. Taken together, this state-of-the-art paradigm may provide useful insights for cancer management by disrupting redox homeostasis.

SUBMITTER: Ren J

PROVIDER: S-EPMC8490505 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Regulated cell death (RCD) has always been considered a tolerogenic event. Immunogenic cell death (ICD) occurs as a consequence of tumour cell death accompanied by the release of damage-associated molecular patterns (DAMPs), triggering an immune response. ICD plays a major role in stimulating the function of the immune system in cancer during chemotherapy and radiotherapy. ICD can therefore represent one of the routes to boost anticancer immune responses. According to the recommendations of the Nomenclature Committee on Cell Death (2018), apoptosis (type I cell death) and necrosis (type II cell death) represent are not the only types of RCD, which also includes necroptosis, pyroptosis, ferroptosis and others. Specific downstream signalling molecules and death-inducing stimuli can regulate distinct forms of ICD, which develop and promote the immune cell response. Dying cells deliver different potential immunogenic signals, such as DAMPs, which are able to stimulate the immune system. The acute exposure of DAMPs can prime antitumour immunity by inducing activation of antigen-presenting cells (APC), such as dendritic cells (DC), leading to the downstream response by cytotoxic T cells and natural killer cells (NK). As ICD represents an important target to direct and develop new pharmacological interventions, the identification of bioactive natural products, which are endowed with low side effects, higher tolerability and preferentially inducing immunogenic programmed cell death, represents a priority in biomedical research. The ability of ICD to drive the immune response depends on two major factors, neither of which is intrinsic to cell death: 'Antigenicity and adjuvanticity'. Indeed, the use of natural ICD-triggering molecules, alone or in combination with different (immuno)therapies, can result in higher efficacy and tolerability. Here, we focused on natural (marine) compounds, particularly on marine microalgae derived molecules such as exopolysaccharides, sulphated polysaccharides, glycopeptides, glycolipids, phospholipids, that are endowed with ICD-inducing properties and sulfavants. Here, we discuss novel and repurposed small-molecule ICD triggers, as well as their ability to target important molecular pathways including the IL-6, TNF-? and interferons (IFNs), leading to immune stimulation, which could be used alone or in combinatorial immunotherapeutic strategies in cancer prevention and therapies.

Project description:As opposed to the standard tolerogenic apoptosis, immunogenic cell death (ICD) constitutes a type of cellular demise that elicits an adaptive immune response. ICD has been characterized in malignant cells following cytotoxic interventions, such as chemotherapy or radiotherapy. Briefly, ICD of cancer cells releases some stress/danger signals that attract and activate dendritic cells (DCs). The latter can then engulf and cross-present tumor antigens to T lymphocytes, thus priming a cancer-specific immunity. This series of reactions works as a positive feedback loop where the antitumor immunity further improves the therapeutic efficacy by targeting cancer cells spared by the cytotoxic agent. However, not all chemotherapeutic drugs currently approved for cancer treatment are able to stimulate bona fide ICD: some commonly used agents, such as cisplatin or 5-fluorouracil, are unable to activate all features of ICD. Therefore, a better characterization of the process could help identify some gene or protein candidates to target pharmacologically and suggest combinations of drugs that would favor/increase antitumor immune response. To this end, we have built a mathematical model of the major cell types that intervene in ICD, namely cancer cells, DCs, CD8+ and CD4+ T cells. Our model not only integrates intracellular mechanisms within each individual cell entity, but also incorporates intercellular communications between them. The resulting cell population model recapitulates key features of the dynamics of ICD after an initial treatment, in particular the time-dependent size of the different cell types. The model is based on a discrete Boolean formalism and is simulated by means of a software tool, UPMaBoSS, which performs stochastic simulations with continuous time, considering the dynamics of the system at the cell population level with appropriate timing of events, and accounting for death and division of each cell type. With this model, the time scales of some of the processes involved in ICD, which are challenging to measure experimentally, have been predicted. In addition, our model analysis led to the identification of actionable targets for boosting ICD-induced antitumor response. All computational analyses and results are compiled in interactive notebooks which cover the presentation of the network structure, model simulations, and parameter sensitivity analyses.

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Ultrasound (US)-activated redox dyshomeostasis therapy reinforced by immunogenic cell death (ICD) through a mitochondrial targeting liposomal nanosystem.

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