Spatiotemporal Targeting Randle Cycle and Immune Checkpoint for Potent Antitumor Therapy

Area of Science:

• Oncology
• Nanotechnology
• Immunotherapy

Background:

• Tumor metabolic reprogramming drives cancer progression and treatment resistance.
• The Randle cycle (glucose-lipid metabolism interplay) complicates single-target metabolic therapies.
• Developing strategies to overcome metabolic crosstalk is critical for effective cancer treatment.

Purpose of the Study:

• To develop a dual metabolic inhibition strategy targeting both glucose and lipid metabolism in tumors.
• To evaluate the efficacy of a glucose oxidase-based nanogel (GOX-NG) combined with a fatty acid oxidation inhibitor (etomoxir, ETX).
• To assess the combined therapy's impact on tumor immunity and overall survival.

Main Methods:

• Fabrication of a catechol-functionalized alginate-based glucose oxidase nanogel (GOX-NG).
• In vivo administration of GOX-NG combined with etomoxir (ETX) and αPD-1 immune checkpoint inhibitor.
• Assessment of tumor penetration, retention, glucose depletion, ROS generation, and immunogenic cell death.
• Evaluation of antitumor immune responses and survival rates in tumor-bearing mice.

Main Results:

• The GOX-NG system demonstrated enhanced tumor penetration, retention, and sustained glucose depletion.
• Dual metabolic suppression (glucose and FAO inhibition) enhanced ROS production and immunogenic cell death.
• Combination therapy with GOX-NG, ETX, and αPD-1 led to complete tumor regression in 60% of animals.
• The triple combination therapy achieved 100% survival in tumor-bearing mice.

Conclusions:

• A synergistic starvation-oxidation-immunotherapy loop effectively treats metastatic tumors.
• Intratumorally-retained nanogels show promise for targeting metabolic pathways in cancer therapy.
• This dual metabolic suppression strategy combined with immunotherapy offers a potent approach for cancer treatment.