Targeting TREM2 to disrupt the mitochondrial lipid and iron metabolism in cisplatin-resistant gastric cancer cells

Abstract

Cancer cells compete with tumor associated macrophages for iron, especially for drug resistant tumor cells. But how drug resistant tumor cells compete with immunosuppressive macrophages in tumor microenvironment is unclear. Here, we identified the triggering receptor expressed on myeloid cells 2 (TREM-2) as a signaling hub that orchestrates lipid and iron metabolism, and immune evasion. TREM-2 was expressed only on cisplatin resistant gastric cancer cell lines, but not on normal gastric epithelial cells and gastric cancer cells. Suppressing TREM2 reversed the drug resistance in vitro and slowed down tumor growth in vivo. Mechanically, TREM2 facilitated TFR1-mediated iron endocytosis to fuel the mitochondria for integrated membrane potential and ATP output. Furthermore, TREM2 knockdown lead to STING upregulation and promote the downstream cytokines IL6, IL-1β secretion. Collectively, our study identified TREM2 as a signaling hub that orchestrates lipid and iron metabolism and immune evasion in cisplatin resistant cells, and explains the complicated metabolic and immune signature for tumor drug resistance.