Abstract <p>Non-small-cell lung cancer (NSCLC) continues to exhibit high mortality largely due to adaptive resistance and metabolic plasticity. Among lipid signaling pathways, ceramide metabolism has emerged as a critical determinant of tumor cell death. Ceramide functions as a stress-responsive lipid mediator that promotes apoptosis, growth arrest, and immunogenic cell death. In NSCLC, however, ceramide signaling is persistently attenuated through enhanced degradation, diversion toward sphingosine-1-phosphate and glycosphingolipid synthesis, and altered intracellular trafficking. This metabolic shift suppresses apoptotic signaling, sustains oncogenic pathways, remodels the tumor microenvironment, and contributes to resistance across chemotherapy, targeted therapy, radiation, and immunotherapy. Unlike mutation-driven resistance, ceramide suppression represents a dynamic metabolic adaptation shared across heterogeneous tumors. Restoring ceramide-centered stress signaling therefore offers a unified strategy to lower apoptotic thresholds and re-sensitize resistant tumors. This review synthesizes mechanistic insights into ceramide dysregulation in NSCLC and examines therapeutic strategies aimed at re-establishing ceramide dominance, including enzyme inhibition, combination-based sensitization, nanocarrier-mediated delivery, and lung-targeted platforms. Finally, a precision framework incorporating lipidomic profiling and biomarker-guided stratification is proposed to facilitate clinical translation. Targeting ceramide metabolism may represent a metabolically informed adjunctive approach to enhance therapeutic durability in NSCLC.</p> Graphical abstract <p></p>