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Simple Summary: Chemotherapy is the major treatment modality for advanced or unresectable hepatocellular carcinoma (HCC). Unfortunately, chemoresistance carries a poor prognosis in HCC patients. Exogenous ceramide, a sphingolipid, has been well documented to exert anticancer effects; however, recent reports showed ceramide resistance, which limits the development of the ceramide-based cancer treatment diTFPP, a novel phenoxyphenol compound that has been shown to sensitize HCC cells to ceramide treatment. Here, we further clarified the mechanism underlying diTFPP-mediated sensitization of HCC to C2-ceramide-induced stresses, including oxidative stress, ER stress, and autophagic stress, especially the modulation of LAMP2 glycosylation, the lysosomal membrane protein that is crucial for autophagic fusion. This study may shed light on the mechanism of ceramide resistance and help in the development of adjuvants for ceramide-based cancer therapeutics. Hepatocellular carcinoma (HCC), the most common type of liver cancer, is the leading cause of cancer-related mortality worldwide. Chemotherapy is the major treatment modality for advanced or unresectable HCC; unfortunately, chemoresistance results in a poor prognosis for HCC patients. Exogenous ceramide, a sphingolipid, has been well documented to exert anticancer effects. However, recent reports suggest that sphingolipid metabolism in ceramide-resistant cancer cells favors the conversion of exogenous ceramides to prosurvival sphingolipids, conferring ceramide resistance to cancer cells. However, the mechanism underlying ceramide resistance remains unclear. We previously demonstrated that diTFPP, a novel phenoxyphenol compound, enhances the anti-HCC effect of C2-ceramide. Here, we further clarified that treatment with C2-ceramide alone increases the protein level of CERS2, which modulates sphingolipid metabolism to favor the conversion of C2-ceramide to prosurvival sphingolipids in HCC cells, thus activating the unfolded protein response (UPR), which further initiates autophagy and the reversible senescence-like phenotype (SLP), ultimately contributing to C2-ceramide resistance in these cells. However, cotreatment with diTFPP and ceramide downregulated the protein level of CERS2 and increased oxidative and endoplasmic reticulum (ER) stress. Furthermore, insufficient LAMP2 glycosylation induced by diTFPP/ceramide cotreatment may cause the failure of autophagosome–lysosome fusion, eventually lowering the threshold for triggering cell death in response to C2-ceramide. Our study may shed light on the mechanism of ceramide resistance and help in the development of adjuvants for ceramide-based cancer therapeutics. [ABSTRACT FROM AUTHOR]