Activating transcription factors: Orchestrators of macrophage biology in pathological settings (Review)

Macrophages, an essential component of the innate immune system, exhibit remarkable plasticity and functional heterogeneity governed by the intricate transcriptional regulatory networks. Activating transcription factors (ATFs) have recently been recognized to modulate multiple signaling pathways, including the MAPK cascades, endoplasmic reticulum stress response and NF‑κB signaling, thereby regulating macrophage biological processes such as inflammatory response, glucose‑lipid metabolism, cellular stress adaptation, autophagy‑apoptosis balance and senescence. By integrating stress signals and metabolic cues, ATF family members construct a sophisticated regulatory network implicated in the pathogenesis of infectious and inflammatory diseases, metabolic disorders, malignancies and neurodegenerative diseases. Therefore, targeted modulations of ATFs or their associated pathways are considered to be capable of precisely regulating macrophage anti‑inflammatory function, metabolic activity and tissue repair capacity in disease settings. Recent technological advances, such as specific targeted delivery systems and gene‑editing strategies, offer promising avenues for the spatiotemporal ATF‑targeting interventions in macrophages, which is critical for improving therapeutic efficacy and safety. The present review systematically summarized recent advances in the understanding of ATF‑mediated regulation of macrophage development, survival, migration, phagocytosis, activation/cytokine secretion, along with polarization and metabolic reprogramming. It also elucidated the pathophysiological implications of these regulatory mechanisms and critically evaluated the clinical feasibility of ATF‑targeted therapeutic interventions.