Lipid metabolic reprogramming of CD8⁺ T cells in the tumor microenvironment

Metabolic reprogramming within the tumor microenvironment is a critical driver of CD8⁺ T cell dysfunction that limits the efficacy of cancer immunotherapy. While glucose and amino acid deprivation are well-characterized, lipid metabolic rewiring has emerged as a fundamental determinant of T cell fate. This review systematically examines the mechanisms by which the tumor microenvironment disrupts CD8⁺ T cell lipid metabolism to promote functional exhaustion and ferroptosis. We first discuss how local stressors such as hypoxia and acidosis alongside systemic host factors including obesity and hyperlipidemia synergistically impose a metabolic siege on infiltrating T cells. We then detail the molecular pathways of dysregulation revealed by recent lipidomic profiling, including CD36-mediated uptake of oxidized lipids that drives ferroptosis, as well as the dysregulation of cholesterol homeostasis that impairs TCR signaling and induces endoplasmic reticulum stress via the IRE1α-XBP1 axis, which directly drives the transcriptional expression of immune checkpoints. Finally, we evaluate therapeutic strategies such as pharmacological modulation of lipid transporters and metabolic engineering of CAR-T cells which hold promise for restoring metabolic fitness and reinvigorating antitumor immunity.