State Key Laboratory of Protein and Plant Gene Research, Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China
Immunotherapies based on immune checkpoint blockade (ICB) have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade. To date, immune checkpoint inhibitors (ICIs) of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy. Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers, however, a large subset of refractory patients presents poor responsiveness to ICB therapy; and the underlying mechanism remains elusive. Recently, numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment (TME) with various products of metabolism, and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy. Nevertheless, a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance. Here, we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints (CTLA-4, PD-1, and PD-L1) to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.
Blockade glutamine with JHU083 (amino acid metabolism)
29F.1A12 (anti PD-1)
Preclinical
[172]
A2AR antagonist CPI-444 (nucleic acid metabolism)
Atezolizumab (anti PD-L1)
Clinical, phase I
[48,49]
Tab.2
Metabolic pathways
Immune checkpoints
Platycodin D inhibits glucose-induced ferroptosis (glycometabolism) [157]
Platycodin D downregulates PD-L1 [156]
NF-κB promotes glycolysis (glycometabolism) [158]
Anti-NF-κB increases ICBs efficacy [159]
TNF-α interferes lipid metabolism [160]
TNF-α upregulates PD-L1 [161]
PI3K/AKT/mTOR (nutrient metabolism) [166]
PI3K/AKT/mTOR upregulates PD-L1 [167]
IL-6/JAK/STAT3 (nutrient metabolism) [166]
Downregulate IL-6/JAK/STAT3 reduces PD-L1 [168]
PI3K (nutrient metabolism) [166]
Blockade of PI3K reduces PD-L1 [170]
MAPK (nutrient metabolism) [166]
Blockade of MAPK increases PD-L1 [171]
Tab.3
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