ATF4 orchestrates cancer hallmarks: Stress adaptation, metabolic reprogramming and immune suppression

Abstract

Summary Activating transcription factor 4 (ATF4) has emerged as a central mediator of cellular stress adaptation, exerting context-dependent and often opposing functions in cancer through the coordinated regulation of metabolism and tumor immunity. However, the mechanistic principles governing ATF4’s functional switch between tumor promotion and suppression remain incompletely defined, and the translational challenges of targeting this pleiotropic transcription factor have not been systematically evaluated. In this review, we dissect the molecular frameworks by which ATF4 integrates stress signals from the endoplasmic reticulum, oxidative stress, and nutrient deprivation to orchestrate metabolic reprogramming and immune evasion. We further critically assess the therapeutic landscape, including pharmacological selectivity, toxicity, and druggability challenges, all of which must be addressed to harness ATF4 as a precision target in oncology.