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Abstract Colorectal cancer (CRC) cells display remarkable adaptability, orchestrating metabolic changes that confer growth advantages, pro‐tumor microenvironment, and therapeutic resistance. One such metabolic change occurs in glutamine metabolism. Colorectal tumors with high glutaminase (GLS) expression exhibited reduced T cell infiltration and cytotoxicity, leading to poor clinical outcomes. However, depletion of GLS in CRC cells has minimal effect on tumor growth in immunocompromised mice. By contrast, remarkable inhibition of tumor growth is observed in immunocompetent mice when GLS is knocked down. It is found that GLS knockdown in CRC cells enhanced the cytotoxicity of tumor‐specific T cells. Furthermore, the single‐cell flux estimation analysis (scFEA) of glutamine metabolism revealed that glutamate‐to‐glutathione (Glu‐GSH) flux, downstream of GLS, rather than Glu‐to‐2‐oxoglutarate flux plays a key role in regulating the immune response of CRC cells in the tumor. Mechanistically, inhibition of the Glu‐GSH flux activated reactive oxygen species (ROS)‐related signaling pathways in tumor cells, thereby increasing the tumor immunogenicity by promoting the activity of the immunoproteasome. The combinatorial therapy of Glu‐GSH flux inhibitor and anti‐PD‐1 antibody exhibited a superior tumor growth inhibitory effect compared to either monotherapy. Taken together, the study provides the first evidence pointing to Glu‐GSH flux as a potential therapeutic target for CRC immunotherapy.
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Crosstalk between Hepatic Glutathione Efflux and Tumor Targeting Efficiency of Indocyanine Green‐Conjugated Gold Nanoparticles
Abstract The elevated glutathione (GSH) level in solid tumors has been used as a major hallmark for GSH‐responsive nanoparticles to enhance targeting efficiency and specificity. Meanwhile, GSH is mainly synthesized inside the hepatocytes of the liver in the body and constantly released into the blood through hepatic GSH efflux to regulate redox potential of the entire body. However, it remains largely unknown how this hepatic GSH efflux affects the tumor targeting of GSH‐responsive nanoparticles. Herein, we report that depletion of hepatic GSH enhanced the tumor targeting of GSH‐responsive indocyanine green‐conjugated Au25nanoclusters coated with 18 GSH ligand (ICG‐Au25SG18). The dissociation of ICG from Au25SG18by the hepatic GSH through thiol‐exchange reaction and the subsequent hepatobiliary clearance of the detached ICG were slowed down by GSH depletion, which in turn prolonged the blood circulation of intact ICG‐Au25SG18and enhanced its tumor targeting. Our work highlights glutathione‐mediated crosstalk between the liver and tumor, in addition to well‐known Kupffer cell‐mediated uptake, in the tumor targeting of engineered nanoparticles, which could be modulated to enhance targeting efficiency and specificity of cancer nanomedicines while reducing their nonspecific accumulation.
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- Award ID(s):
- 2018188
- PAR ID:
- 10471311
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Angewandte Chemie International Edition
- Volume:
- 62
- Issue:
- 45
- ISSN:
- 1433-7851
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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