Ceramide-mediated immunometabolic modulation in hepatocellular carcinoma (HCC): emerging functions of sphingomyelin phosphodiesterase 3 (SMPD3).
Abstract
Hepatocellular carcinoma (HCC) develops within a metabolically constrained and immunologically heterogeneous tumor microenvironment in which malignant, stromal, and immune cells compete for nutrients and exchange bioactive metabolites. Ceramide is a main sphingolipid intermediate and signaling lipid with several biological effects, which depend on acyl-chain composition, subcellular localization, metabolic flux, and cellular context. Sphingomyelin phosphodiesterase 3 (SMPD3), also known as neutral sphingomyelinase 2 (nSMase2), generates ceramide through sphingomyelin hydrolysis and also participates in extracellular-vesicle biogenesis. HCC-specific findings claimed that reduced SMPD3 expression could be associated with adverse clinicopathological features and suppression of malignant phenotypes after SMPD3 restoration, could be in favor of a tumor-restraining function. However, direct evidence that endogenous SMPD3-derived ceramide reprograms the metabolism of infiltrating immune cells in primary HCC is currently lacking. This review distinguishes HCC-specific findings from mechanistic evidence derived from tumor and inflammatory systems. We integrate ceramide biosynthesis and turnover, HCC immunometabolism, T-cell and myeloid-cell metabolic states, extracellular-vesicle communication, and therapeutic studies using ceramide nanoliposomes. We also discuss the context-dependent relationship between ceramide and apoptosis, autophagy, mitochondrial dysfunction, and ferroptosis, emphasizing that endogenous SMPD3-derived ceramide and exogenous short-chain ceramide formulations are not biologically interchangeable. Finally, we define experimental priorities required to test cell-specific SMPD3 functions, resolve ceramide species and spatial flux, validate biomarkers, and determine whether selective restoration of the SMPD3-ceramide axis can improve immunotherapy or other systemic treatment strategies in HCC.
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