Sphingolipids, including ceramide and sphingosine-1-phosphate (S1P), play opposing roles in cancer cell death and survival. Recent studies have elucidated how sphingolipid metabolism and signaling regulate these processes in response to anticancer therapy. Ceramide induces apoptosis, necroptosis, and mitophagy, while S1P promotes cell survival and tumor growth. Sphingolipid metabolism is regulated by enzymes such as sphingosine kinase 1 and 2, which convert ceramide to S1P. S1P signaling through its receptors (S1PR1–5) influences cancer cell proliferation, migration, and metastasis. Targeting sphingolipid metabolism and signaling has shown promise in cancer therapy, with clinical trials evaluating the efficacy of enzymes that catabolize ceramide or generate S1P. Sphingolipid metabolism is also involved in tumor immunology, with S1P signaling affecting immune cell function and tumor progression. Sphingolipid metabolism is regulated by various enzymes, including SPT, CERS1–6, DES, SMases, SMS, CERT, CERK, GCS, CDases, and SPHK1/2. These enzymes influence cancer cell survival, drug resistance, and tumor metastasis. Sphingolipid metabolism is also linked to cancer immunotherapy, with S1P signaling affecting immune cell egress and antitumor functions. Overall, sphingolipid metabolism is a key regulatory pathway in cancer biology and therapy, with potential therapeutic strategies targeting sphingolipid metabolism and signaling.Sphingolipids, including ceramide and sphingosine-1-phosphate (S1P), play opposing roles in cancer cell death and survival. Recent studies have elucidated how sphingolipid metabolism and signaling regulate these processes in response to anticancer therapy. Ceramide induces apoptosis, necroptosis, and mitophagy, while S1P promotes cell survival and tumor growth. Sphingolipid metabolism is regulated by enzymes such as sphingosine kinase 1 and 2, which convert ceramide to S1P. S1P signaling through its receptors (S1PR1–5) influences cancer cell proliferation, migration, and metastasis. Targeting sphingolipid metabolism and signaling has shown promise in cancer therapy, with clinical trials evaluating the efficacy of enzymes that catabolize ceramide or generate S1P. Sphingolipid metabolism is also involved in tumor immunology, with S1P signaling affecting immune cell function and tumor progression. Sphingolipid metabolism is regulated by various enzymes, including SPT, CERS1–6, DES, SMases, SMS, CERT, CERK, GCS, CDases, and SPHK1/2. These enzymes influence cancer cell survival, drug resistance, and tumor metastasis. Sphingolipid metabolism is also linked to cancer immunotherapy, with S1P signaling affecting immune cell egress and antitumor functions. Overall, sphingolipid metabolism is a key regulatory pathway in cancer biology and therapy, with potential therapeutic strategies targeting sphingolipid metabolism and signaling.