Long non-coding RNA prompts immune-related adverse events risk and immunotherapy response in pan-cancer

Immune checkpoint inhibitors (ICIs) improve cancer outcomes but can cause immune-related adverse events (irAEs) that compromise treatment. Using FAERS real-world data, we developed a two-layer network algorithm to identify irAE-associated lncRNAs (irAEsLncs) across 18 cancer types. The irAEsLnc network showed organ-specific patterns and cancer-specific irAE susceptibility, while irAEsLncs were associated with immune infiltration, inflammatory responses, immune activation, and checkpoint molecules. Single-cell analysis of ICI-induced colitis linked irAEsLncs to inflammatory macrophage and T cell states and metabolic reprogramming. irAEsLnc-derived signatures independently predicted prognosis and responses to targeted therapy and immunotherapy, with ALAL-1/CD80/MEF2C predicting ICI efficacy in lung adenocarcinoma. Knockdown of ALAL-1 and SEC61G-DT suppressed tumor cell proliferation, migration, invasion, and macrophage-mediated inflammation. These findings connect irAE-associated lncRNAs with toxicity and antitumor immunity and support their potential as biomarkers for treatment stratification.