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Laubach et al. Cancer Drug Resist 2023;6:611-41  https://dx.doi.org/10.20517/cdr.2023.60                                         Page 631

               Table 1. Tumor-intrinsic metabolic targets, the resulting metabolites, and the drug or compound used against the target that have
               been evaluated pre-clinically and/or clinically in combination with anti-PD-1/PD-L1 therapy
                                                                                  Combination with
                Target (metabolite)       Drug/Compound           Pre-clinical or clinical       Ref.
                                                                                  anti-PD-1/PD-L1
                ALKBH5 (lactate)          ALK-04                  Pre-clinical    Anti-PD-1      [42]
                LDHA (lactate)            GSK2837808A             Pre-clinical    Anti-PD-1      [43]
                HCAR1 (lactate)           3-OBA                   Pre-clinical    Anti-PD-1      [44]
                A2AR (adenosine)          CPI-444                 Clinical        Anti-PD-L1     [84]
                A2AR (adenosine)          DZD2269                 Pre-clinical    Anti-PD-1      [85]
                CD39 (adenosine)          IPH5201                 Clinical        Anti-PD-L1     [89]
                CD39 (adenosine)          IPH5201                 Pre-clinical    Anti-PD-L1     [88-90]
                CD39 (adenosine)          TTX-030                 Clinical        Anti-PD-1      [91]
                CD73 (adenosine)          MEDI9447 (oleclumab)    Clinical        Anti-PD-L1     [92,93]
                A2AR (adenosine)          Nanoreactor             Pre-clinical    Anti-PD-1      [94]
                CD39 (adenosine)          POM-1                   Pre-clinical    Anti-PD-1      [95]
                CD39 (adenosine)          ARL67156                Pre-clinical    Anti-PD-1      [96]
                       +
                CD38 (NAD )               Anti-CD38 and RHein     Pre-clinical    Anti-PD-L1     [114]
                ARG1 (arginine)           Vaccine                 Pre-clinical    Anti-PD-1      [156]
                ARG1/2 (arginine)         OATD-02                 Pre-clinical    Anti-PD-1      [150,160-162]
                ARG (arginine)            CB-1158                 Clinical        Anti-PD-1      [163-165]
                SLC1A5 (glutamine)        V-9302                  Pre-clinical    Anti-PD-L1     [183]
                Glutamine-utilizing enzymes (glutamine) JHU083    Pre-clinical    Anti-PD-1      [184]
                YTHDF1 (methionine)       Short-hairpin knockdown of YTHDF1 Pre-clinical  Anti-PD-L1  [202]
                SLC43A2 (methionine)      BCH                     Pre-clinical    Anti-PD-L1     [203]
                ACAT1 (cholesterol)       CI-1011                 Pre-clinical    Anti-PD-1      [236]
                PCSK9 (cholesterol)       AMG-145 and D10335      Pre-clinical    Anti-PD-1      [227]

               ACAT1: Acyl-CoA cholesterol acyl transferase 1; ALKBH5: alkB homolog 5; ARG1: arginase 1; A2AR: adenosine A2A receptor; HCAR1:
               hydroxycarboxylic acid receptor 1; LDHA: lactate dehydrogenase A; PCSK9: proprotein convertase subtilisin/kexin type 9; PD-L1: programmed cell
               death ligand 1; PD-1: programmed cell death protein 1; SLC: solute carrier; YTHDF1: YTH N6-methyladenosine RNA binding protein F1.

               PERSPECTIVES
               In recent years, immense strides have been made in studying the intersection of metabolism, cancer, and the
               immune system. In addition to the metabolites and pathways covered in this review, there are a plethora of
               others waiting to be linked to CD8  T cell dysfunction and ICB resistance. For example, other amino acids
                                             +
               and lipid classes, metabolites produced by the gut microbiome, and a closer look at the metabolites
               associated with oxidative phosphorylation and ATP production. Moreover, there is much to uncover about
               how tumor-derived metabolic alterations affect other immune and non-immune cell types. Continued
               research efforts in this field will provide a more comprehensive understanding of tumor-intrinsic metabolic
               alterations and reveal nuanced ways to target tumor metabolism and overcome resistance to ICB therapies.


               DECLARATIONS
               Acknowledgments
               We thank AbbVie employees Eugene Nyamugenda, PhD, Fedik Rahimov, PhD, and Cyril Ramathal, PhD,
               for reviewing the manuscript and providing insightful suggestions.

               Authors’ contributions
               Writing-original draft: Laubach K
               Writing-review and editing: Laubach K, Turan T, Mathew R, Wilsbacher J, Engelhardt J, Samayoa J
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