KLF5-driven TAZ-FASN signaling reprograms fatty acid metabolism to support Treg differentiation in lung cancer

Metabolic reprogramming is a fundamental hallmark of cancer and provides essential biochemical support for malignant progression. In lung cancer, aberrant fatty acid metabolism not only fuels cancer cell growth but also influences regulatory T cell (Treg) differentiation through altered lipid availability. Krüppel-like factor 5 (KLF5) has been implicated in lung cancer progression; however, its role in coordinating cancer fatty acid metabolism and Treg differentiation remains insufficiently defined.

We combined clinical lung cancer specimens, genetically modified lung cancer cell models, Treg differentiation systems, and mouse tumor models to define the metabolic function of KLF5. Gain- and loss-of-function approaches were used to determine how KLF5 affects lipid storage, fatty acid synthesis, extracellular free fatty acid production, and tumor growth. Conditioned-medium transfer experiments, fatty acid uptake assays, fatty acid oxidation measurements, and flow cytometry were applied to evaluate the impact of cancer cell-derived lipid output on Treg differentiation. Mechanistically, promoter-binding assays, transcriptional reporter analysis, protein-interaction experiments, molecular docking, and TAZ depletion were used to dissect how KLF5 regulates FASN-dependent fatty acid synthesis.

KLF5 was highly expressed in lung cancer tissues and cells and showed positive associations with lipogenic markers and Treg-related indicators. Suppression of KLF5 markedly weakened the fatty acid metabolic phenotype of lung cancer cells, as reflected by reduced lipid droplet accumulation, decreased free fatty acid release, and downregulation of FASN, SCD1, DGAT2, and PLIN5. In vivo, KLF5 knockdown restrained tumor growth and reduced fatty acid synthesis-related molecular features. Mechanistically, KLF5 bound directly to the FASN promoter and cooperated with TAZ to enhance FASN transcription. KLF5 promoted nuclear accumulation of TAZ, whereas TAZ silencing attenuated KLF5-induced FASN expression, lipid accumulation, and free fatty acid production. Functionally, fatty acids released from KLF5-overexpressing lung cancer cells enhanced CD36-associated fatty acid uptake and fatty acid oxidation in Tregs, thereby promoting Treg differentiation. Conversely, KLF5 depletion reduced this lipid-associated differentiation process both in vitro and in tumor-bearing mice.

This study reveals a KLF5-driven fatty acid metabolic program in lung cancer. KLF5 cooperates with TAZ to activate FASN transcription, thereby increasing lipogenesis and free fatty acid release. The resulting lipid output promotes CD36-dependent fatty acid uptake and oxidation in Tregs and supports their differentiation. These findings identify the KLF5-TAZ-FASN axis as a cancer metabolism-centered mechanism linking lung cancer lipogenesis to Treg differentiation, highlighting this pathway as a potential metabolic vulnerability for interfering with fatty acid-supported lung cancer progression.