Inhibition of Glutamate‐to‐Glutathione Flux Promotes Tumor Antigen Presentation in Colorectal Cancer Cells

• DOI: 10.1002/advs.202310308
• Publication Date: 2024-11-01T06:39:26Z
• Authors: Tao Yu; Kevin Van der Jeught; Haiqi Zhu; Zhuolong Zhou; Samantha Sharma; Sheng Liu; Haniyeh Eyvani; Ka Man So; Naresh Singh; Jia Wang; George E. Sandusky; Yunlong Liu; Mateusz Opyrchal; Sha Cao; Jun Wan; Chi Zhang; Xinna Zhang
• Keywords: Glutaminase

Abstract Colorectal cancer (CRC) cells display remarkable adaptability, orchestrating metabolic changes that confer growth advantages, pro‐tumor microenvironment, and therapeutic resistance. One such change occurs in glutamine metabolism. tumors with high glutaminase (GLS) expression exhibited reduced T cell infiltration cytotoxicity, leading to poor clinical outcomes. However, depletion of GLS CRC has minimal effect on tumor immunocompromised mice. By contrast, inhibition is observed immunocompetent mice when knocked down. It found knockdown enhanced the cytotoxicity tumor‐specific cells. Furthermore, single‐cell flux estimation analysis (scFEA) metabolism revealed glutamate‐to‐glutathione (Glu‐GSH) flux, downstream GLS, rather than Glu‐to‐2‐oxoglutarate plays a key role regulating immune response tumor. Mechanistically, Glu‐GSH activated reactive oxygen species (ROS)‐related signaling pathways cells, thereby increasing immunogenicity by promoting activity immunoproteasome. The combinatorial therapy inhibitor anti‐PD‐1 antibody superior inhibitory compared either monotherapy. Taken together, study provides first evidence pointing as potential target for immunotherapy.