Long non-coding RNAs as regulators of immune signaling pathways in esophageal cancer.

Despite advances in immunotherapy, significant challenges remain in the treatment of esophageal cancer (EC), largely due to its molecular complexity and the immunosuppressive tumor microenvironment (TME). Recently, long non-coding RNAs (lncRNAs) have emerged as critical regulators of tumor immunity, influencing key pathways involved in inflammation, immune evasion, and therapeutic response. In this review, we examine the role of immune-related lncRNAs in modulating major immunological signaling pathways in EC, including Programmed Cell Death Protein 1/Programmed Death-Ligand 1 (PD-1/PD-L1), Toll-Like Receptor (TLR), Tumor Necrosis Factor-alpha (TNF-α), Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB), and Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathways. Oncogenic lncRNAs such as LINC02096, Cancer Susceptibility Candidate 9 (CASC9), and Small Nucleolar RNA Host Gene 20 (SNHG20) promote immune checkpoint expression, facilitating immune escape and resistance to checkpoint blockade. Other lncRNAs, including LINC02820, NSUN2-methylated lncRNA (NMR), and Myeloid-Associated Long Non-coding RNA (MALR), activate TNF-α/NF-κB signaling, contributing to inflammation-driven metastasis. Additionally, MALAT1 and FAM83H-AS1 regulate transforming growth factor-beta (TGF-β)-mediated epithelial-to-mesenchymal transition, enhancing tumor progression. Conversely, NF-κB Interacting Long Non-coding RNA (NKILA) functions as a tumor suppressor by inhibiting NF-κB activation. Importantly, lncRNA expression profiles correlate with immune checkpoint levels, immune cell infiltration, and patient survival, highlighting their potential as biomarkers for prognosis and therapeutic response. This review provides a framework for understanding lncRNA-mediated immune regulation and supports their translational potential in EC immunotherapy.