Palmitic acid and palmitoylation in cancer: Understanding, insights, and challenges

Nutrients from dietary foods not only provide energy and building blocks, but also play critical roles in modulating diverse pathophysiological functions. They achieve these, in part, by accelerating cell signaling transduction processes via modulating various types of protein post-translational modifications (PTMs). Notably, accumulating evidence has identified palmitic acid (PA), a major component of high-fat diets, as a significant contributor to various human disorders, including diabetes and cancer. Hence, further understanding the roles of PA and its involvement in protein palmitoylation, a key PTM, is crucial for uncovering the mechanisms underlying these diseases and exploring potential clinical applications in cancer therapy. This review comprehensively summarizes recent advances in the understanding of PA homeostasis and palmitoylation in tumorigenesis. Specifically, it highlights the connections between palmitoylation and key processes such as oncogenic signaling pathways, cell death mechanisms, innate immune responses, and the tumor microenvironment. The review also emphasizes potential therapeutic strategies, including targeting PA homeostasis, palmitoylation-associated processes, or specific palmitoylated proteins for cancer treatment. Finally, the challenges in the field, such as the regulation of PA homeostasis and the dynamic detection or targeting of palmitoylation, are discussed, underscoring the need for further research to address these critical issues.