Mitochondrial immune regulation and anti-tumor immunotherapy strategies targeting mitochondria

Bai, Rilan; Cui, Jiuwei

doi:10.1016/j.canlet.2023.216223

Cited by 21 publications

(14 citation statements)

References 111 publications

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“…In our study, we found that ESM1 regulates lipid remodeling by inducing the Warburg effect through PKM2 and regulating AMPK/mTOR signaling through ATP production. Previous studies have generally suggested that solid tumor cells use glycolysis to circumvent the TCA cycle or mitochondrial dysfunction for rapid productivity [ 48 – 50 ]. Additionally, cancer cells utilize VM, a biological process that mimics blood vessels and connects to normal vascular endothelial cells, to obtain additional nutrients and oxygen [ 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

ESM1 enhances fatty acid synthesis and vascular mimicry in ovarian cancer by utilizing the PKM2-dependent warburg effect within the hypoxic tumor microenvironment

Zhang,

Ouyang,

Gao

et al. 2024

Mol Cancer

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Background The hypoxic tumor microenvironment is a key factor that promotes metabolic reprogramming and vascular mimicry (VM) in ovarian cancer (OC) patients. ESM1, a secreted protein, plays an important role in promoting proliferation and angiogenesis in OC. However, the role of ESM1 in metabolic reprogramming and VM in the hypoxic microenvironment in OC patients has not been determined. Methods Liquid chromatography coupled with tandem MS was used to analyze CAOV3 and OV90 cells. Interactions between ESM1, PKM2, UBA2, and SUMO1 were detected by GST pull-down, Co-IP, and molecular docking. The effects of the ESM1-PKM2 axis on cell glucose metabolism were analyzed based on an ECAR experiment. The biological effects of the signaling axis on OC cells were detected by tubule formation, transwell assay, RT‒PCR, Western blot, immunofluorescence, and in vivo xenograft tumor experiments. Results Our findings demonstrated that hypoxia induces the upregulation of ESM1 expression through the transcription of HIF-1α. ESM1 serves as a crucial mediator of the interaction between PKM2 and UBA2, facilitating the SUMOylation of PKM2 and the subsequent formation of PKM2 dimers. This process promotes the Warburg effect and facilitates the nuclear translocation of PKM2, ultimately leading to the phosphorylation of STAT3. These molecular events contribute to the promotion of ovarian cancer glycolysis and vasculogenic mimicry. Furthermore, our study revealed that Shikonin effectively inhibits the molecular interaction between ESM1 and PKM2, consequently preventing the formation of PKM2 dimers and thereby inhibiting ovarian cancer glycolysis, fatty acid synthesis and vasculogenic mimicry. Conclusion Our findings demonstrated that hypoxia increases ESM1 expression through the transcriptional regulation of HIF-1α to induce dimerization via PKM2 SUMOylation, which promotes the OC Warburg effect and VM.

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Section: Discussionmentioning

confidence: 99%

ESM1 enhances fatty acid synthesis and vascular mimicry in ovarian cancer by utilizing the PKM2-dependent warburg effect within the hypoxic tumor microenvironment

Zhang,

Ouyang,

Gao

et al. 2024

Mol Cancer

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“…For instance, metabolic interventions that promote the glycolytic or mitochondrial pathways in TILs can improve their persistence and effector functions in the tumor microenvironment. 100,101 When combining immunometabolism and immunotherapy, it is essential to consider timing, dosage, and administration order.…”

Section: Combination Therapies: Immunometabolism and Immunotherapymentioning

confidence: 99%

“…By modulating the metabolism of these infused immune cells, their survival and antitumor activity can be enhanced. For instance, metabolic interventions that promote the glycolytic or mitochondrial pathways in TILs can improve their persistence and effector functions in the tumor microenvironment 100,101 …”

Section: Strategies For Enhancing Immune Responsementioning

confidence: 99%

Discovering the strength of immunometabolism in cancer therapy: Employing metabolic pathways to enhance immune responses

Huldani,

Malviya,

Rodrigues

et al. 2024

Cell Biochemistry & Function

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Immunometabolism, which studies cellular metabolism and immune cell function, is a possible cancer treatment. Metabolic pathways regulate immune cell activation, differentiation, and effector functions, crucial to tumor identification and elimination. Immune evasion and tumor growth can result from tumor microenvironment metabolic dysregulation. These metabolic pathways can boost antitumor immunity. This overview discusses immune cell metabolism, including glycolysis, oxidative phosphorylation, amino acid, and lipid metabolism. Amino acid and lipid metabolic manipulations may improve immune cell activity and antitumor immunity. Combination therapy using immunometabolism‐based strategies may enhance therapeutic efficacy. The complexity of the metabolic network, biomarker development, challenges, and future approaches are all covered, along with a summary of case studies demonstrating the effectiveness of immunometabolism‐based therapy. Metabolomics, stable isotope tracing, single‐cell analysis, and computational modeling are also reviewed for immunometabolism research. Personalized and combination treatments are considered. This review adds to immunometabolism expertise and sheds light on metabolic treatments' ability to boost cancer treatment immunological response. Also, in this review, we discussed the immune response in cancer treatment and altering metabolic pathways to increase the immune response against malignancies.

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“…In addition, mitochondrial dysfunction is increasingly recognized as a contributing factor to immune escape mechanisms in the tumor microenvironment ( 30 , 51 ). Mitochondria influence the tumor microenvironment by regulating inflammatory responses and cytokine production, which in turn affects immune cell infiltration and activity ( 13 , 31 ).…”

Section: Pancreatic Cancer and Mitochondrial Functionmentioning

confidence: 99%

“…Mitochondria influence the tumor microenvironment by regulating inflammatory responses and cytokine production, which in turn affects immune cell infiltration and activity ( 13 , 31 ). Therefore, in some tumors, the anti-tumor immune response is weakened due to impaired mitochondrial function, providing favorable conditions for tumor cell escape and proliferation ( 30 ).…”

Section: Pancreatic Cancer and Mitochondrial Functionmentioning

confidence: 99%

Illuminating the immunological landscape: mitochondrial gene defects in pancreatic cancer through a multiomics lens

Chi,

Su,

Yan

et al. 2024

Front. Immunol.

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This comprehensive review delves into the complex interplay between mitochondrial gene defects and pancreatic cancer pathogenesis through a multiomics approach. By amalgamating data from genomic, transcriptomic, proteomic, and metabolomic studies, we dissected the mechanisms by which mitochondrial genetic variations dictate cancer progression. Emphasis has been placed on the roles of these genes in altering cellular metabolic processes, signal transduction pathways, and immune system interactions. We further explored how these findings could refine therapeutic interventions, with a particular focus on precision medicine applications. This analysis not only fills pivotal knowledge gaps about mitochondrial anomalies in pancreatic cancer but also paves the way for future investigations into personalized therapy options. This finding underscores the crucial nexus between mitochondrial genetics and oncological immunology, opening new avenues for targeted cancer treatment strategies.

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Mitochondrial immune regulation and anti-tumor immunotherapy strategies targeting mitochondria

Cited by 21 publications

References 111 publications

ESM1 enhances fatty acid synthesis and vascular mimicry in ovarian cancer by utilizing the PKM2-dependent warburg effect within the hypoxic tumor microenvironment

ESM1 enhances fatty acid synthesis and vascular mimicry in ovarian cancer by utilizing the PKM2-dependent warburg effect within the hypoxic tumor microenvironment

Discovering the strength of immunometabolism in cancer therapy: Employing metabolic pathways to enhance immune responses

Illuminating the immunological landscape: mitochondrial gene defects in pancreatic cancer through a multiomics lens

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