ArticleExperimental & molecular medicine2022
Inhibition of phospholipase D1 induces immunogenic cell death and potentiates cancer immunotherapy in colorectal cancer.
Article in Experimental & molecular medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 32 citations in OpenAlex.
- Iron-Tannic Acid Hydrogel Mediated Mild Photothermal Therapy Combined With Ferroptosis Enhances Anti-Tumor Immunity in Colorectal Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- PLD1 and PLD2 promote an immunosuppressive tumor microenvironment via CCL19-dependent macrophage polarization and PD-L1 induction.Experimental & molecular medicine · 2026Article
- Exclusion of Notch from the contact site during efferocytosis restricts anticancer immunity.Nature immunology · 2026Article
- The significance of immunogenic cell death related prognostic gene markers in colorectal cancer prognosis and antitumor immunity.Scientific reports · 2026Article
- Exploring the Relationship Between Colitis-Associated Cancer and Lipid Metabolism Reprogramming from the Perspective of Inflammation-Cancer Transformation.Journal of inflammation research · 2026Review
- Recent advances in novel targeting mechanisms for colorectal cancer.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Phospholipase D: emerging therapeutic targets in signaling, metabolism, and immune-oncology.Cell communication and signaling : CCS · 2025Review
- Lipid metabolic reprogramming in colorectal cancer: Insights to mechanisms and therapeutics.World journal of gastrointestinal oncology · 2025Review
- Phospholipase D6 activates Wnt/β-catenin signaling through mitochondrial metabolic reprogramming to promote tumorigenesis in colorectal cancer.Experimental & molecular medicine · 2025Article
- Development and Evaluation of Indole-Based Phospholipase D Inhibitors for Lung Cancer Immunotherapy.Journal of medicinal chemistry · 2025Article
- Phospholipase D1 is a critical mediator of neutrophil extracellular trap formation and venous thrombosis.Frontiers in immunology · 2025Article
- Effects of phospholipase D1-inhibitory peptide on the growth and metastasis of gastric cancer cells.Molecules and cells · 2024Article
- Therapeutic strategies of targeting non-apoptotic regulated cell death (RCD) with small-molecule compounds in cancer.Acta pharmaceutica Sinica. B · 2024Review
- PLD1 is a key player in cancer stemness and chemoresistance: Therapeutic targeting of cross-talk between the PI3K/Akt and Wnt/β-catenin pathways.Experimental & molecular medicine · 2024Review
- Phospholipase D, a Novel Therapeutic Target Contributes to the Pathogenesis of Neurodegenerative and Neuroimmune Diseases.Analytical cellular pathology (Amsterdam) · 2024Review
- Pathogenic single nucleotide polymorphisms in RhoA gene: Insights into structural and functional impacts on RhoA-PLD1 interaction through molecular dynamics simulation.Current research in structural biology · 2024Article
- Clinical application of immunogenic cell death inducers in cancer immunotherapy: turning cold tumors hot.Frontiers in cell and developmental biology · 2024Review
- An overview of the mechanisms and potential roles of extracellular vesicles in septic shock.Frontiers in immunology · 2023Review
- Exosome Secretion and Epithelial-Mesenchymal Transition in Ovarian Cancer Are Regulated by Phospholipase D.International journal of molecular sciences · 2022Article
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Phospholipase D (PLD) is a potential therapeutic target against cancer. However, the contribution of PLD inhibition to the antitumor response remains unknown. We developed a potent and selective PLD1 inhibitor based on computer-aided drug design. The inhibitor enhanced apoptosis in colorectal cancer (CRC) cells but not in normal colonic cells, and in vitro cardiotoxicity was not observed. The inhibitor downregulated the Wnt/β-catenin signaling pathway and reduced the migration, invasion, and self-renewal capacity of CRC cells. In cancer, therapeutic engagement of immunogenic cell death (ICD) leads to more effective responses by eliciting the antitumor immunity of T cells. The CRC cells treated with the inhibitor showed hallmarks of ICD, including downregulation of "do not eat-me" signals (CD24, CD47, programmed cell death ligand 1 [PD-L1]), upregulation of "eat-me" signal (calreticulin), release of high-mobility group Box 1, and ATP. PLD1 inhibition subsequently enhanced the phagocytosis of cancer cells by macrophages through the surface expression of costimulatory molecules; as a result, the cancer cells were more susceptible to cytotoxic T-cell-mediated killing. Moreover, PLD1 inhibition attenuated colitis-associated CRC and orthotopically injected tumors, probably by controlling multiple pathways, including Wnt signaling, phagocytosis checkpoints, and immune signaling. Furthermore, combination therapy with a PLD1 inhibitor and an anti-PD-L1 antibody further enhanced tumor regression via immune activation in the tumor environment. Collectively, in this study, PLD1 was identified as a critical regulator of the tumor microenvironment in colorectal cancer, suggesting the potential of PLD1 inhibitors for cancer immunotherapy based on ICD and immune activation. PLD1 inhibitors may act as promising immune modulators in antitumor treatment via ICD.
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