The emerging landscape of lncRNAs in gastric cancer immunity: From immune escape to ferroptosis and metabolic reprogramming.

Gastric cancer (GC) remains a major global health challenge, particularly in East Asia, and the clinical impact of immune checkpoint inhibitors is limited by prevalent immune evasion and heterogeneous tumor immune microenvironments (TIME). Long noncoding RNAs (lncRNAs) have rapidly emerged as critical regulators of these processes, functioning far beyond their originally presumed nonfunctional roles. Through intricate interactions with chromatin regulators, RNA-binding proteins, microRNAs, metabolic enzymes, and RNA modification machinery, lncRNAs orchestrate diverse pathways that collectively shape antitumor immunity in GC. Recent studies have revealed that lncRNAs modulate PD-L1 expression, govern the recruitment and polarization of immunosuppressive cells such as regulatory T cells and M2 macrophages, and alter cytokine and chemokine signaling to create immune-tolerant niches. In parallel, ferroptosis-related, metabolism-associated, and hypoxia-responsive lncRNAs-such as AC129507.1, CBSLR, NR_033928, and HCP5-link metabolic rewiring with immune suppression by regulating lipid peroxidation, glutamine utilization, fatty acid oxidation, and redox homeostasis. Additional layers of immune modulation arise from autophagy-, senescence-, and apoptosis-associated lncRNAs, which influence immunogenic cell death, stress adaptation, and inflammatory secretomes. Epitranscriptomic regulation, including m6A- and m5C-dependent modulation of lncRNA stability and function, further integrates p53 signaling with immune control. Together, these findings establish lncRNAs as master regulators of immune escape, therapeutic resistance, and TIME remodeling in gastric cancer. Advances in multi-omics profiling and RNA-targeted drug delivery now offer promising avenues to exploit lncRNAs as biomarkers for prognosis and immunotherapy response, as well as therapeutic targets capable of sensitizing tumors to ICIs, ferroptosis induction, and metabolic interventions. Continued mechanistic and translational research will be essential to fully harness the potential of lncRNA-directed precision immunotherapy for gastric cancer.