Metabolic Implications of Immune Checkpoint Proteins in Cancer

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Abstract
Expression of immune checkpoint proteins restrict immunosurveillance in the tumor microenvironment; thus, FDA-approved checkpoint inhibitor drugs, specifically PD-1/PD-L1 and CTLA-4 inhibitors, promote a cytotoxic antitumor immune response. Aside from inflammatory signaling, immune checkpoint proteins invoke metabolic reprogramming that affects immune cell function, autonomous cancer cell bioenergetics, and patient response. Therefore, this review will focus on the metabolic alterations in immune and cancer cells regulated by currently approved immune checkpoint target proteins and the effect of costimulatory receptor signaling on immunometabolism. Additionally, we explore how diet and the microbiome impact immune checkpoint blockade therapy response. The metabolic reprogramming caused by targeting these proteins is essential in understanding immune-related adverse events and therapeutic resistance. This can provide valuable information for potential biomarkers or combination therapy strategies targeting metabolic pathways with immune checkpoint blockade to enhance patient response.
Funding Information
  • American Cancer Society (133727-RSG-19-150-01-LIB)
  • V Foundation for Cancer Research (V2019-018)
  • National Cancer Institute (R21CA249349)
  • National Institute of Allergy and Infectious Diseases (5T32AI007401)
  • National Institutes of Health (T32-OD010957)
  • ASTRO-BCRF (637969)

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