MoS2 Reshapes the Tumor Microenvironment to Promote Tumor Cell Ferroptosis
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ABSTRACT:
PROVIDER: PRJNA1055446 | ENA |
REPOSITORIES: ENA
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Project description:MoS2 has found application in various biomedical fields, such as bioimaging and drug delivery. Nonetheless, utilizing MoS2 for anti-tumor therapy remains challenging, especially tumor immunotherapy. Macrophages, pivotal constituents of the tumor microenvironment, play a crucial role in driving tumor progression and chemoresistance. Modulating macrophages to reshape this microenvironment stands as a promising avenue for effective tumor treatment. In this study, we unveil a mechanism by which MoS2 induces the metamorphosis of macrophages from an M0 to an M1 phenotype, thus altering the tumor microenvironment. This transformation triggers pathways associated with inflammation within M1-type macrophages, leading to an upsurge in the expression of inflammatory molecules like IL1β. Macrophages activated by MoS2 exhibit a propensity to impede tumor cell proliferation. Through comprehensive RNA-sequencing analysis, we noted that MoS2 induces a greater enrichment of differentially expressed genes in the cytokine release pathway within macrophages. The excessive secretion of IL1β by MoS2-activated macrophages emerges as a pivotal catalyst, heightening ROS levels and decreasing GSH levels within tumor cells, ultimately culminating in ferroptosis. Therefore, we suggest MoS2 effectively reshapes the tumor microenvironment by steering macrophages toward releasing inflammatory molecules. The MoS2-triggered activation of macrophages, inducing the secretion of IL1β, emerges as a potent trigger for ferroptosis within tumor cells. Consequently, MoS2 holds substantial promise as an efficacious strategy for anti-tumor immunotherapy, achieved through the polarization of macrophages.
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Project description:Ferroptosis is a non-apoptotic form of regulated cell death triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. The development of the concept of ferroptosis stemmed from an active search for alternatives to apoptosis in cancer cells. Ferroptosis inducers have shown remarkable effectiveness in killing tumor cells in vitro, yet with no obvious success in experimental animal models, with a notable exception of immune-deficient mice 1,2. This suggests the potential poorly understood contribution of ferroptosis on immune cells. Pathologically activated neutrophils (PMN), termed myeloid-derived suppressor cells (PMN-MDSC), are major negative regulators of anti-tumor immunity3-5. Here, we found that PMN-MDSC in the tumor microenvironment (TME), spontaneously die by ferroptosis. While decreasing the presence of PMN-MDSC, ferroptosis induces the release of oxygenated lipids and limits mouse and human T cell activity. In immune-competent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSC, reduces tumor progression, and synergizes with immune checkpoint blockade (ICB) to suppress the tumor growth. In contrast, induction of ferroptosis in immune-competent mice promotes tumor growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSC in the TME that can be pharmacologically modulated to limit tumor progression.
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Project description:Ferroptosis is a non-apoptotic form of regulated cell death triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. The development of the concept of ferroptosis stemmed from an active search for alternatives to apoptosis in cancer cells. Ferroptosis inducers have shown remarkable effectiveness in killing tumor cells in vitro, yet with no obvious success in experimental animal models, with a notable exception of immune-deficient mice 1,2. This suggests the potential poorly understood contribution of ferroptosis on immune cells. Pathologically activated neutrophils (PMN), termed myeloid-derived suppressor cells (PMN-MDSC), are major negative regulators of anti-tumor immunity3-5. Here, we found that PMN-MDSC in the tumor microenvironment (TME), spontaneously die by ferroptosis. While decreasing the presence of PMN-MDSC, ferroptosis induces the release of oxygenated lipids and limits mouse and human T cell activity. In immune-competent mice, genetic and pharmacological inhibition of ferroptosis abrogates suppressive activity of PMN-MDSC, reduces tumor progression, and synergizes with immune checkpoint blockade (ICB) to suppress the tumor growth. In contrast, induction of ferroptosis in immune-competent mice promotes tumor growth. Thus, ferroptosis is a unique and targetable immunosuppressive mechanism of PMN-MDSC in the TME that can be pharmacologically modulated to limit tumor progression.
2022-09-19 | GSE205371 | GEO
Project description:Immune checkpoint blockade (ICB) triggers tumor ferroptosis. However, most patients are unresponsive to ICB. Tumors might evade ferroptosis in the tumor microenvironment (TME). Here, we discovered SLC13A3 is an itaconate transporter in tumor cells and endows tumor ferroptosis resistance, diminishing tumor immunity and ICB efficacy. Mechanistically, tumor cells uptake itaconate via SLC13A3 from tumor-associated macrophages (TAMs), thereby activating the NRF2-SLC7A11 pathway and escaping from immune-mediated ferroptosis. Structural modeling and molecular docking analysis identified a functional inhibitor for SLC13A3 (SLC13A3i). Deletion of ACOD1 (an essential enzyme for itaconate synthesis) in macrophages, genetic ablation of SLC13A3 in tumors, or treatment with SLC13A3i sensitized tumors to ferroptosis, curbed tumor progression, and bolstered ICB effectiveness. Thus, we identify the interplay between tumors and TAMs via the SLC13A3-itaconate-NRF2-SLC7A11 axis as a previously unknown immune ferroptosis resistant mechanism in the TME and SLC13A3 as a promising immunometabolic target and disease indication for treating SLC13A3+cancer.
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Project description:Immune checkpoint blockade (ICB) triggers tumor ferroptosis. However, most patients are unresponsive to ICB. Tumors might evade ferroptosis in the tumor microenvironment (TME). Here, we discovered SLC13A3 is an itaconate transporter in tumor cells and endows tumor ferroptosis resistance, diminishing tumor immunity and ICB efficacy. Mechanistically, tumor cells uptake itaconate via SLC13A3 from tumor-associated macrophages (TAMs), thereby activating the NRF2-SLC7A11 pathway and escaping from immune-mediated ferroptosis. Structural modeling and molecular docking analysis identified a functional inhibitor for SLC13A3 (SLC13A3i). Deletion of ACOD1 (an essential enzyme for itaconate synthesis) in macrophages, genetic ablation of SLC13A3 in tumors, or treatment with SLC13A3i sensitized tumors to ferroptosis, curbed tumor progression, and bolstered ICB effectiveness. Thus, we identify the interplay between tumors and TAMs via the SLC13A3-itaconate-NRF2-SLC7A11 axis as a previously unknown immune ferroptosis resistant mechanism in the TME and SLC13A3 as a promising immunometabolic target and disease indication for treating SLC13A3+cancer.
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Project description:Compared to the well-established roles of apoptosis in tumor suppression, the roles and regulatory mechanisms of ferroptosis, a non-apoptotic form of cell death, in tumor biology remain much less understood. BRCA1-associated protein 1 (BAP1) encodes a nuclear de-ubiquitinating (DUB) enzyme to reduce histone 2A ubiquitination (H2Aub) on chromatin, and is a tumor suppressor in several human cancers. Here, integrated transcriptomic, epigenomic, and cancer genomic analyses link BAP1 to metabolism-related biological processes, including oxidative stress response, and identify cystine transporter SLC7A11 as a BAP1-repressed target gene with high relevance to BAP1-mediated tumor suppression in human cancers. Functional studies reveal that BAP1, in a DUB-dependent manner, decreases H2Aub occupancy on the SLC7A11 promoter and represses SLC7A11 expression, and that BAP1 inhibits cystine uptake and promotes ferroptosis through repressing SLC7A11 expression. Finally, we show that BAP1 inhibits tumor development partly through SLC7A11, and that cancer-associated BAP1 mutants lose their abilities to repress SLC7A11 and to promote ferroptosis. Together, the results of our study show that BAP1 executes its tumor suppression function at least partly through its regulation of SLC7A11 and ferroptosis, and uncover a previously unappreciated mechanism coupling ferroptosis to tumor suppression.
2018-07-05 | GSE101987 | GEO
Project description:In vivo macrophage engineering reshapes the tumor microenvironment leading to eradication of liver metastases [Visium]
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