A metabolic intervention strategy to break evolutionary adaptability of tumor for reinforced immunotherapy

Area of Science:

• Oncology
• Immunology
• Nanotechnology
• Metabolic Engineering

Background:

• Tumor evolution is characterized by metabolic dysregulation, impacting both tumor and immune cells.
• Tumor cells and immune cells exhibit distinct metabolic pathways and plasticity, creating therapeutic opportunities.
• Harnessing metabolic differences offers a strategy to eliminate tumor and immunosuppressive cells while boosting beneficial immune cells.

Purpose of the Study:

• To develop a novel nanoplatform for cancer immunotherapy by targeting tumor cell metabolism.
• To investigate the efficacy of a cerium metal-organic framework (CeMOF)-based nanoplatform (CLCeMOF) in modulating the tumor microenvironment and immune responses.
• To explore the combined strategy of lactate depletion and glutamine antagonism for enhanced cancer treatment.

Main Methods:

• Development of a CLCeMOF nanoplatform by modifying cerium metal-organic framework (CeMOF) with lactate oxidase (LOX) and loading glutaminase inhibitor (CB839).
• Induction of cascade catalytic reactions by CLCeMOF to generate reactive oxygen species and deplete lactate.
• Application of immunometabolic checkpoint blockade therapy via glutamine antagonism.

Main Results:

• CLCeMOF induced a reactive oxygen species 'storm' to elicit immune responses.
• Lactate exhaustion by LOX relieved the immunosuppressive tumor microenvironment.
• CLCeMOF inhibited glutamine metabolism-dependent cells, increased dendritic cell infiltration, and reprogrammed CD8+ T lymphocytes into an activated, long-lived, memory-like phenotype.

Conclusions:

• The CLCeMOF nanoplatform effectively intervenes in both metabolite and cellular metabolic pathways.
• This metabolic intervention strategy alters cell fates, inhibiting tumor growth and enhancing anti-tumor immunity.
• The approach holds promise for breaking tumor evolutionary adaptability and reinforcing immunotherapy.