Internal medicine

Enzyme

Glycolysis

Tumor microenvironment

Oxidative stress

Immunotherapy

Immunogenic cell death

Hexokinase

Cancer immunotherapy

Biology

Cancer

Prodrug

Apoptosis

Chemistry

Immunology

Immunosuppression

Programmed cell death

Glutathione

Oxidative phosphorylation

Metabolism

Cell biology

Cancer research

Biochemistry

Medicine

Intracellular

Immune system

Cancer cell

Pharmacology

Nano Letters

Blocking energy metabolism of cancer cells and simultaneously stimulating the immune system to perform immune attack are significant for cancer treatment. However, how to potently deliver different drugs with these functions remains a challenge. Herein, we synthesized a nanoprodrug formed by a F127-coated drug dimer to inhibit glycolysis of cancer cells and alleviate the immunosuppressive microenvironment. The dimer was delicately constructed to connect lonidamine (LND) and NLG919 by a disulfide bond which can be cleaved by excess GSH to release two drugs. LND can decrease the expression of hexokinase II and destroy mitochondria to restrain glycolysis for energy supply. NLG919 can reduce the accumulation of kynurenine and the number of regulatory T cells, thus alleviating the immunosuppressive microenvironment. Notably, the consumption of GSH by disulfide bond increased the intracellular oxidative stress and triggered immunogenic cell death of cancer cells. This strategy can offer more possibilities to explore dimeric prodrugs for synergistic cancer therapy.

GSH-Responsive Nanoprodrug to Inhibit Glycolysis and Alleviate Immunosuppression for Cancer Therapy