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

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.