fig4

Figure 4. Summary schematic of how altered tumor-intrinsic energy, amino acid, and lipid metabolism drive CD8⁺ T cell dysfunction and resistance to anti-PD-1/PD-L1 treatment. Targets in red are described in the previous sections and modulating these targets overcomes resistance to anti-PD-1/PD-L1 therapy. ACAT1: Acyl-CoA cholesterol acyl transferase 1; Ado: adenosine; ALKBH5: alkB homolog 5, RNA demethylase; Arg: arginine; ARG1: arginase 1; ATX: autotaxin; A2AR: adenosine A2A receptor; CD8⁺: CD⁺ T cell; CHL: cholesterol; FAs: fatty acids; Gln: glutamine; GLS: glutaminase; Glu: glutamate; HCAR1: hydroxycarboxylic acid receptor 1; LD: lipid droplet; LDHA: lactate dehydrogenase A; LDL: low-density lipoprotein; LDLR: low-density lipoprotein receptor; LPA: lysophosphatidic acid; LPAR5: lysophosphatidic acid receptor 5; LPC: lysophosphatidylcholine; MCT: monocarboxylate transporter; Me: methyl; Met: methionine; NAD⁺: nicotinamide adenine dinucleotide; Orn: ornithine; PCSK9: proprotein convertase subtilisin/kexin type 9; PD-L1: programmed cell death ligand 1; PD-1: programmed cell death protein 1; SAM: S-adenosylmethionine; SLC: solute carrier; Tex: CD8⁺ T cell exhaustion; Treg: T regulatory cell; YTHDF1: YTH N6-methyladenosine RNA binding protein F1.