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<p>The phospholipase D (PLD) family, comprising six evolutionarily conserved isoforms (PLD1-6), serves as master regulators of lipid signaling, membrane dynamics, and cellular communication. Functional divergence driven by structural heterogeneity enables PLD-mediated control of signal transduction, metabolic homeostasis, and immune responses. Activated by stimuli like growth factors and hormones, PLD governs core signaling networks, including Wnt/β-catenin, protein kinase C (PKC), and mammalian target of rapamycin (mTOR) pathways while modulating glucose uptake and lipid metabolism. PLD isoforms coordinate adaptive and innate immunity through T/B cell activation, macrophage polarization, and cytokine regulation. Dysregulated PLD activity promotes metabolic syndrome, autoimmune diseases, and remodeling of the tumor immune microenvironment, positioning PLD as a therapeutic target. This review integrates isoform-specific mechanisms in signaling, metabolism, immunity and tumor microenvironment, and underscores the critical need for isoform-specific inhibitors to dissect pathological mechanisms and advance disease understanding. By deconvoluting PLD’s pleiotropic roles across signaling axis, lipid-glucose crosstalk, and immune circuitry, this work delineates a roadmap for developing targeted combinatorial therapies that exploit PLD’s spatial-temporal regulation of cellular homeostasis.</p> Graphical Abstract <p>The phospholipase D (PLD) enzyme family serves as a central regulatory node governing interconnected biological processes, including cellular signal transduction, metabolic reprogramming, and immunomodulatory networks, particularly within tumor-immune microenvironment dynamics. A comprehensive understanding of PLD's molecular underpinnings in these cascades holds significant translational potential for developing targeted therapies against cancer, autoimmune disorders, and metabolic diseases.</p> <p></p>

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Phospholipase D: emerging therapeutic targets in signaling, metabolism, and immune-oncology

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月20日

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  • Lin Tang,
  • Yunxiao Ge,
  • Yuanying Li,
  • Xiaobing Chen,
  • Kangdong Liu,
  • Zigang Dong,
  • Hui Liu

摘要

The phospholipase D (PLD) family, comprising six evolutionarily conserved isoforms (PLD1-6), serves as master regulators of lipid signaling, membrane dynamics, and cellular communication. Functional divergence driven by structural heterogeneity enables PLD-mediated control of signal transduction, metabolic homeostasis, and immune responses. Activated by stimuli like growth factors and hormones, PLD governs core signaling networks, including Wnt/β-catenin, protein kinase C (PKC), and mammalian target of rapamycin (mTOR) pathways while modulating glucose uptake and lipid metabolism. PLD isoforms coordinate adaptive and innate immunity through T/B cell activation, macrophage polarization, and cytokine regulation. Dysregulated PLD activity promotes metabolic syndrome, autoimmune diseases, and remodeling of the tumor immune microenvironment, positioning PLD as a therapeutic target. This review integrates isoform-specific mechanisms in signaling, metabolism, immunity and tumor microenvironment, and underscores the critical need for isoform-specific inhibitors to dissect pathological mechanisms and advance disease understanding. By deconvoluting PLD’s pleiotropic roles across signaling axis, lipid-glucose crosstalk, and immune circuitry, this work delineates a roadmap for developing targeted combinatorial therapies that exploit PLD’s spatial-temporal regulation of cellular homeostasis.

Graphical Abstract

The phospholipase D (PLD) enzyme family serves as a central regulatory node governing interconnected biological processes, including cellular signal transduction, metabolic reprogramming, and immunomodulatory networks, particularly within tumor-immune microenvironment dynamics. A comprehensive understanding of PLD's molecular underpinnings in these cascades holds significant translational potential for developing targeted therapies against cancer, autoimmune disorders, and metabolic diseases.