Metabolic and inflammatory reprogramming of macrophages by ONC201 translates in a pro‐inflammatory environment even in presence of glioblastoma cells

Abstract

Tumor‐associated macrophages facilitate tumor progression and resistance to therapy. Their capacity for metabolic and inflammatory reprogramming represents an attractive therapeutic target. ONC201/TIC10 is an anticancer molecule that antagonizes the dopamine receptor D2 and affects mitochondria integrity in tumor cells. We examined whether ONC201 induces a metabolic and pro‐inflammatory switch in primary human monocyte‐derived macrophages that reactivates their antitumor activities, thus enhancing the onco‐toxicity of ONC201. Contrary to glioblastoma cells, macrophages exhibited a low ratio of dopamine receptors D2/D5 gene expression and were resistant to ONC201 cytotoxicity. Macrophages responded to ONC201 with a severe loss of mitochondria integrity, a switch to glycolytic ATP production, alterations in glutamate transport, and a shift towards a pro‐inflammatory profile. Treatment of macrophages–glioblastoma cells co‐cultures with ONC201 induced similar alterations in glutamatergic and inflammatory gene expression profiles of macrophages. It induced as well metabolic changes and a pro‐inflammatory switch of the co‐culture milieu. However, these changes did not translate into increased onco‐toxicity. This study provides the first evidence that ONC201 affects macrophage immunometabolism and leads to a pro‐inflammatory tumor environment. This speaks in favor of implementing ONC201 in combinatorial therapies and warrants further investigation of the mechanisms of action of ONC201 in macrophages and other immune cells.