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Page 612 Laubach et al. Cancer Drug Resist 2023;6:611-41 https://dx.doi.org/10.20517/cdr.2023.60

INTRODUCTION
The development of immune checkpoint blockade (ICB) therapies revolutionized cancer treatment across a
variety of indications. Immune checkpoints are necessary for the controlled initiation and termination of
immune responses as well as for the maintenance of self-tolerance, which are critical in preventing
[1]
autoimmunity . However, tumors leverage this checkpoint system to inappropriately dampen the immune
[1]
response and facilitate immune escape . Continuous antigen stimulation drives the upregulation of
+
[2]
checkpoint receptors on CD8 T cells , while tumor cells exploit a variety of mechanisms to upregulate
checkpoint ligands. Therefore, blocking the interaction between immune checkpoint receptors and ligands
reinvigorates CD8 T cell function to elicit tumor cell killing. There are several ICB therapies that are
+
currently utilized in the clinic, but the most well-studied are anti-programmed cell death protein 1
(anti-PD-1), which is predominantly found on T cells, and anti-programmed cell death ligand 1
(anti-PD-L1), which is expressed on tumor and myeloid cells . While anti-PD-1/PD-L1 treatments
[3]
are widely used, a substantial number of patients are resistant to this type of therapy , prompting
[4]
researchers to identify resistance mechanisms that drive inadequate outcomes. Response to ICB is largely
+
dependent on the existing profile and infiltration of immune cells within the tumor, specifically CD8 T
cells, because they are the main contributors to anti-tumor effects . Therefore, modulating
[4]
+
the tumor-immune microenvironment (TIME) to enhance CD8 T cell infiltration and function, in
combination with current ICB therapies, serves as an attractive approach to increase efficacy and overcome
resistance.

The intersection of cancer and metabolism has been at the forefront of oncology research for several
decades. Otto Warburg and his identification of the Warburg effect, wherein malignant cells exhibit a
[5]
metabolic shift from oxidative phosphorylation to glycolysis , ignited massive research efforts towards
uncovering the metabolic reprogramming that occurs in tumors. These efforts led to the classification of
dysregulated tumor cell metabolism as one of the hallmarks of cancer in 2022 . Therefore, altered
[6]
metabolism of lipids, amino acids, carbon, and nucleotides, to name a few, are highly implicated in the
development and progression of cancer . More recently, this field of onco-metabolism has expanded to
[7]
include the immune system, given its role in regulating tumorigenesis. Immune cells and their subtypes
[8]
have different metabolic requirements during activation, differentiation, and expansion , wherein
alterations in the extrinsic metabolome at any of these stages can lead to immune cell dysfunction. The
TIME is an objectively harsh environment for many cell types due to its acidity, hypoxia, nutrient
[9]
deprivation, and accumulation of inhibitory metabolites . To the advantage of the tumor, malignant and
immunosuppressive cells, such as T regulatory cells (Tregs), myeloid-derived suppressor cells (MDSCs),
and macrophages, are better adapted to this oppressive environment compared to anti-tumor CD8 T
+
cells . These conditions, which are largely facilitated by cancer cells, heavily contribute to decreased CD8 +
[10]
T cell infiltration and function.

There is mounting evidence that tumor-intrinsic metabolic reprogramming has a profound effect on the
recruitment and function of various immune cell types within the TIME. As such, it is necessary to identify
ways to specifically target malignant cell metabolism to enhance the efficacy of ICB. The scope of this review
article will aim to cover the current literature that demonstrates how tumor-derived alterations in energy,
amino acid, and lipid metabolism within the TIME mediate CD8 T cell dysfunction and how targeting
+
these pathways combats resistance to anti-PD-L1/PD-1 treatment.

ENERGY METABOLISM
Energy metabolism includes a complex network of biochemical pathways that contribute to sustained
cellular function through the production of adenosine triphosphate (ATP). Some of these processes include
glycolysis, the tricarboxylic acid (TCA) cycle, and fatty acid b-oxidation. A shift in energy metabolism