Recent advancements in immunotherapy spotlight the pivotal role of macrophages in disease treatment. The polarization of macrophages, wherein these immune cells differentiate into either pro-inflammatory (M1) or anti-inflammatory (M2) states, plays a vital role in the therapeutic modulation of a spectrum of diseases. Oligonucleotides have emerged as potent tools for modulating macrophage polarization with high specificity and potential cost-effectiveness compared to traditional therapies. In this review, we delve into the application of oligonucleotides for steering macrophage polarization, introducing how macrophage is polarized and how 4 different kinds of oligonucleotide (ASO, siRNA, agomir/antagomir and aptamer) works, discusses their therapeutic potentials and challenges associated with these strategies, emphasizing the importance of precise, disease-specific interventions by presenting actual examples. While the application of oligonucleotides in clinical faces challenges, we also highlights some recent, significant advances in current trials and the future potential in stimulating macrophages for therapeutic advantages in immunotherapy, signaling a frontier in disease treatment and management.
