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Laubach et al. Cancer Drug Resist 2023;6:611-41 https://dx.doi.org/10.20517/cdr.2023.60 Page 623

Many cancers exhibit a dependence on or addiction to glutamine. As such, increased glutaminolysis is
highly important for ATP production, redox homeostasis, and activation of various oncogenic signaling
[168]
pathways in tumor cells [168-170] . Glutamine fuels KRAS signaling in pancreatic adenocarcinoma , mTORC1
[170]
signaling in osteosarcoma and cervical cancer cells , and promotes lipid biogenesis under hypoxic
conditions to provide additional energy sources . Hypoxia also drives the mitochondrial import of
[171]
glutamine to support ATP and glutathione production to combat oxidative stress and promote uncontrolled
cell growth . Interestingly, data suggest that some cancers will adapt to the glutamine-deprived TIME and
[172]
will cease to rely on glutamine. In patient-derived melanoma tumors, for example, excess dietary glutamine
inhibits cell growth .
[173]

[174]
T cells require glutamine for a variety of functions during differentiation and development ; thus, there is
stiff competition between tumor cells and T cells for glutamine consumption. Ligation of CD3 and CD28 on
T cells induces glutamine uptake via ERK and calcineurin pathways to sustain T cell activation,
proliferation, and cytokine production [175,176] . Interestingly, glutamine is also required for glucose uptake and
glycolysis in activated CD8 T cells, and proper effector functions were dependent on both glucose and
+
glutamine . As such, increasing glutamine availability for T cells, while depriving tumor cells and
[177]
immunosuppressive cells, has strong anti-tumor effects. For example, selectively inhibiting glutamine
uptake in triple-negative breast cancer cells increased CD8 T cell activation and effector function by
+
[178]
promoting glutathione production . On the other hand, non-specific intracellular depletion of glutamine
[179]
+
leads to impaired mitochondrial function and CD8 T cell apoptosis , likely due to increased oxidative
damage from reduced glutathione production. Data also suggest the temporal importance of glutamine
availability in driving T cell function. During TCR stimulation, glutamine deprivation decreases PD-1 and
increases Ki67 expression , suggesting that glutamine abundance needs to be tightly regulated at various
[180]
stages of T cell development to ensure proper functionality. As discussed in previous sections,
immunosuppressive cells largely thrive in the nutrient-deprived TIME. Specifically, tumor-associated
macrophages respond to low glutamine levels by secreting IL-23 to promote Treg proliferation and
+
[181]
activation, resulting in diminished CD8 T cell function .
Several reports have demonstrated that inhibiting tumor-associated glutamine metabolism in combination
+
with anti-PD-1/PD-L1 therapies may be a promising approach to restore CD8 T cell function and
overcome resistance. Because glutamine deprivation promotes T cell dysfunction, specifically inhibiting
glutamine metabolism in tumor cells would yield the most efficacious results. Two separate groups found
that glutamine deprivation in cell lines of human clear cell renal carcinoma , human non-small cell lung
[182]
carcinoma , and mouse colorectal carcinoma induced PD-L1 expression, which would theoretically
[183]
[183]
boost anti-PD-L1 response. Byun et al. found that anti-PD-L1 monotherapy had almost no effect on tumor
volume in murine colorectal carcinoma models . However, tumor-specific inhibition of glutamine uptake
[183]
+
and glutaminase activity in combination with anti-PD-L1 therapy strongly induced CD8 T cell
[183]
proliferation and granzyme B production, while abating tumor growth . Similarly, another group targeted
tumor-derived glutamine enzymes by creating a prodrug that is only activated by TIME-restricted enzymes
[184]
to limit the cytotoxic effects of systemic glutamine antagonism . This treatment method decreased
glycolysis in malignant cells, decreased hypoxia, acidosis, and nutrient depletion within the TIME, and
[184]
increased activation of and oxidative phosphorylation in CD8 T cells . In combination with anti-PD-1
+
therapy, tumor-specific glutamine antagonism synergistically reduced tumor growth and increased survival
[184]
in murine colorectal carcinoma tumors . Conversely, employing a non-tumor cell specific glutaminase
inhibitor does not yield the same efficacious results. Serine/threonine kinase 11 (STK11) phosphorylates
AMPK to regulate a variety of downstream pathways, such as cell growth and proliferation, lipid
[185]
metabolism, and PD-L1 expression . Several studies have shown that STK11 mutations, resulting in loss