Acyl-CoA thioesterases and their derived lipid mediators: linking Acyl-CoA metabolic reprogramming to the tumor microenvironment.

Metabolic reprogramming in tumors is a fundamental mechanism by which tumor cells adapt to proliferative stress and evade immune surveillance. In recent years, the regulatory role of lipid metabolism-particularly acyl-CoA metabolism-within the tumor microenvironment has garnered increasing attention. As a central hub of lipid metabolism, acyl-CoA homeostasis directly determines cellular energy status, membrane lipid composition, and signal output. The acyl-CoA thioesterase (ACOT) family regulates intracellular homeostasis of free fatty acids (FFAs) and acyl-CoA by hydrolyzing the thioester bond of acyl-CoA, thereby influencing membrane lipid composition, ferroptosis sensitivity, and immune cell function, and consequently promoting tumor progression, drug resistance, and microenvironmental remodeling. In this context, this review systematically summarizes the structural and functional characteristics of the ACOT family, elucidates the regulatory networks of its derived lipid mediators in tumors, and describes its effects on tumor metabolism and the microenvironment through interactions with other metabolic enzymes. This review aims to reveal the pivotal role of the ACOT family in the tumor metabolism-immunity network, update our understanding of its complex roles in tumors, and provide theoretical insights and future research directions for its potential as a drug target and for overcoming treatment resistance.