Targeting lncRNA-regulated macrophage polarization: a novel therapeutic strategy for pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC), which is the most common type of pancreatic cancer (PC), carries a poor prognosis with a 5-year survival rate of less than 12%. Suboptimal therapeutic responses are primarily attributed to the immunosuppressive features of the tumor microenvironment (TME). In the PDAC TME, tumor-associated macrophages (TAMs) constitute the dominant immune cell population. Polarization of TAMs toward the M2 phenotype promotes tumor progression, immune escape, therapeutic resistance, and disease advancement. Recent studies have demonstrated that long non-coding RNAs (lncRNAs) regulate M2-TAM polarization and PDAC progression via transcriptional, epigenetic, and post-transcriptional mechanisms. This review summarizes key lncRNAs involved in TAM polarization in PDAC, highlighting their roles in inducing the M2 phenotype and promoting PDAC progression through epigenetic modifications, ceRNA networks, and signal transduction pathways. Based on these regulatory mechanisms, potential therapeutic strategies targeting lncRNAs, such as siRNA-mediated knockdown, CRISPR-based editing, antisense oligonucleotides, downstream-targeting strategies, and nanoparticle delivery systems, may provide more precise control over lncRNA activity to repolarize TAMs and reverse immunosuppression in the TME. Furthermore, advances in developing clinical prognostic models that incorporate lncRNAs linked to M2-TAMs offer potential for refined patient outcome prediction and the identification of tailored PDAC treatment options.