The sphingolipid code of cancer: divergent roles across tumor types and therapeutic horizons

Sphingolipids have emerged as critical bioactive molecules that orchestrate diverse cellular processes underlying cancer initiation, progression, and therapeutic resistance. Once considered structural membrane lipids, they are now recognized as dynamic regulators of proliferation, apoptosis, angiogenesis, metastasis, and immune evasion. Central to this biology is the ceramide and sphingosine-1-phosphate (S1P) balance, a metabolic switch that dictates cell fate between death and survival. However, accumulating evidence reveals that the "sphingolipid code" is cancer-type specific, shaped by the expression of distinct enzyme isoforms, metabolite profiles, and microenvironmental contexts. This review consolidates current knowledge on sphingolipid alterations across major malignancies, including hematological cancers, colorectal, gastric, pancreatic, breast, ovarian, endometrial, lung, glioblastoma, and melanoma. We have highlighted emerging common mechanistic themes, such as the roles of gangliosides in metastasis and chemoresistance driven by glucosylceramide synthase. Furthermore, we have discussed the therapeutic horizons of targeting sphingolipid metabolism, ranging from sphingosine kinase (SphK1/2) inhibitors and ceramide delivery systems to ganglioside-directed immunotherapy, with emphasis on preclinical and clinical advancements. By integrating sphingolipid biology with precision oncology frameworks, sphingolipids hold a promise as both therapeutic targets and biomarkers. Yet, challenges such as tumor heterogeneity, drug delivery barriers, and toxicity must be overcome to achieve positive clinical translations. Deciphering the sphingolipid code across cancers offers a transformative opportunity to unlock novel strategies for diagnosis, prognosis, and treatment, ultimately bridging basic lipid biology with personalized cancer therapy.