RELL2 (RELT like 2) is a tumor necrosis factor receptor family member that functions as a modulator of RELT signaling at the plasma membrane 1. When overexpressed, RELL2 induces activation of the MAPK14/p38 cascade and triggers apoptosis through a death pathway distinct from classical TNFRs like TNFR1 2. The p38 activation involves OSR1 and TRAF2 signaling intermediates 2. In pancreatic ductal adenocarcinoma, RELL2 exhibits anti-oncogenic properties, suppressing cell proliferation and gemcitabine resistance through intron 4 retention regulation by DHX38 3. However, pan-cancer analysis reveals paradoxical expression patterns: high RELL2 expression correlates with poor prognosis, increased tumor mutational burden, and enhanced immune checkpoint gene expression across multiple cancers 4. In breast cancer, RELL2 functions as an anti-metastatic factor via miR-18a-mediated regulation 5. The gene's role varies contextually—RELT knockout mice show enhanced anti-tumor T cell responses, suggesting RELL2 may promote immunosuppression in certain contexts 6. Additionally, genetic polymorphism rs14251 at the RELL2 locus associates with methamphetamine dependence vulnerability 7, indicating broader physiological relevance beyond cancer.