The ATF4-glutamine axis: a central node in cancer metabolism, stress adaptation, and therapeutic targeting

Abstract

At the center of tumor(neoplasm) metabolic adaptation lies activating transcription factor 4 (ATF4), a key regulator that orchestrates Glutamine (Gln) uptake, utilization, and redox balance under conditions of nutrient deprivation and oxidative stress. This review explores how ATF4 integrates environmental and cellular stress signals to drive Gln metabolic processes, enabling tumor survival, metabolic reprogramming, and immune evasion. The ATF4-Gln axis emerges as a pivotal vulnerability in cancer metabolic processes. Preclinical studies of small-molecule inhibitors and synthetic derivatives disrupting this pathway show promising results. Understanding the intricate interplay between ATF4, Gln metabolic processes, and cancer progression provides valuable insights for novel therapeutic strategies. Future research must address tumor heterogeneity and metabolic flexibility to fully harness the potential of ATF4-centered therapies. However, challenges such as off-target effects of ATF4 inhibitors and metabolic plasticity in tumors remain critical barriers. Future studies integrating multi-omics approaches and AI-driven drug discovery are warranted to overcome these hurdles.