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Page 622 Laubach et al. Cancer Drug Resist 2023;6:611-41 https://dx.doi.org/10.20517/cdr.2023.60

because they do not express ASS1 [136,137] , meaning they must compete with tumor cells and
immunosuppressive cells for arginine.

T cell function is highly disrupted by arginine depletion within the TIME, which is mediated by both
malignant cells [138-141] and immunosuppressive cells [142-147] . In T cells, arginine is important in regulating CD3z
expression, which is necessary for proper antigen recognition by the TCR-CD3 complex [148-151] . For example,
ARG2-dependent depletion of arginine by murine renal cell carcinoma cells leads to decreased expression of
CD3z in T cells . Sufficient arginine levels are also necessary during T cell activation because arginine is
[139]
[152]
quickly metabolized to fuel downstream processes . Moreover, decreased systemic arginine levels in Lewis
lung carcinoma and arginine depletion via ARG1 from cancer-derived exosomes in ovarian
[150]
+
[153]
carcinoma inhibit antigen-specific proliferation of CD8 TILs. Arginine depletion also impairs the
effector function of CD8 T cells by preventing the secretion of IFNg and granzyme B [154,155] . On the other
+
hand, arginine supplementation in CD8 T cells induces metabolic rewiring from glycolysis towards
+
oxidative phosphorylation to promote proliferation, survival, and anti-tumor responses .
[152]
Several promising pre-clinical studies have demonstrated that targeting arginine metabolism in
combination with anti-PD-1/PD-L1 treatment increases efficacy in overcoming resistance. Employing
anti-PD-1 treatment in combination with vaccine inhibition of ARG1 synergistically impaired tumor
growth and led to increased CD8 T cell infiltration in mouse models of colorectal carcinoma and
+
fibrosarcoma . Further, systemic arginine supplementation with anti-PD-1 or PD-L1 treatment increased
[156]
CD8 T cell infiltration and exhibited more efficacious results than monotherapy in mouse models of colon
+
[157]
carcinoma and osteosarcoma . Utilizing a unique approach, researchers engineered an E. coli strain
[158]
that localizes to the TIME and converts ammonia to arginine . This innovative method promoted
[159]
+
continuous arginine supplementation in murine colorectal carcinoma tumors, leading to increased CD8 T
cell infiltration and synergistic anti-tumor effects when combined with anti-PD-L1 treatment . Extensive
[159]
pre-clinical studies for a novel ARG1/2 inhibitor (OATD-02) have shown promising results alone and in
combination with both anti-PD-1 and -PD-L1, and researchers are hopeful this drug will enter first-in-
human clinical trials soon [150,160-162] . Moreover, the ARG1 inhibitor CB-1158 entered first-in-human clinical
trials in 2017 and was evaluated with anti-PD-1 treatment [163-165] . The results indicate that CB-1158
monotherapy and combination with anti-PD-1 are well-tolerated and elicit a response in solid tumors [163-165] .

A considerable amount of evidence demonstrates that tumor-mediated depletion of arginine negatively
impacts CD8 T cell function and the anti-tumor response. Additionally, the enhanced anti-tumor effects
+
seen by combining anti-PD-1/PD-L1 with ARG inhibitors or arginine supplementation demonstrate that
altering tumor metabolism could have profound effects on the efficacy of ICB. However, continued pre-
clinical and clinical efforts are necessary to identify additional ways to target tumor-derived arginine
metabolism and reinvigorate the anti-tumor immune response to improve ICB.

Glutamine
Glutamine has many essential functions, such as supporting the formation of nucleotides and non-essential
amino acids, protein synthesis, energy metabolism, and maintaining intracellular redox states . Import of
[166]
glutamine is facilitated by many transporters, predominantly SLC1A5 [136,167] [Figure 2]. Once inside the cell,
glutamine is transported to the mitochondria to be converted to glutamate via glutaminase enzymes . In
[166]
the cytosol, glutamate serves as a precursor for glutathione synthesis, which is a strong antioxidant . The
[166]
metabolism of glutamine also drives the formation of NADPH, which is critical for restoring the
intracellular redox balance by reducing oxidized glutathione . In the mitochondria, glutamate is converted
[168]
to a-Ketoglutarate to drive the TCA cycle .
[166]