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Laubach et al. Cancer Drug Resist 2023;6:611-41 https://dx.doi.org/10.20517/cdr.2023.60 Page 625

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through m A methylation, whereby the RNA-binding protein YTHDF1 enhances the translation efficiency
[202]
of RNA containing m A methylation . While anti-PD-1 treatment alone in mouse colorectal carcinoma
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tumors did not significantly alter tumor volume or CD8 T cell infiltration, depletion of YTHDF1 or
+
restricting methionine in the diet synergized with anti-PD-1 treatment to significantly increase survival
probability and CD8 T cell infiltration, while decreasing tumor volume . Similarly, the second study
[202]
+
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found that methionine-dependent histone methylation regulates CD8 T cell anti-tumor activities.
Methionine deprivation in CD8 T cells resulted in reduced H3K79me2 methylation and subsequent STAT5
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expression , which is a critical transcription factor that maintains CD8 T cell effector functions . In
[204]
[203]
vitro, methionine supplementation increased CD8 T cell survival and IFNg and TNFa production, while
+
[203]
inhibiting murine melanoma tumor growth . The authors also found that SLC43A2 and SLC7A5 import
methionine in malignant cells, but T cells are predominantly dependent on SLC7A5 . As such, genetic
[203]
ablation of SLC43A2 in mouse melanoma cells restored CD8 T cell polyfunctionality and survival in vitro,
+
and decreased tumor growth in vivo . While anti-PD-1 treatment or pharmacological inhibition of
[203]
SLC43A2 alone did not elicit significant anti-tumor effects, combination treatment synergistically increased
[203]
+
CD8 T cell function and infiltration, and decreased growth of mouse melanoma and ovarian tumors .
These data demonstrate that resistance to anti-PD-1 treatment can be negated by restricting methionine
availability and metabolism in tumors.
Taken together, the studies in this section have undoubtedly established that targeting amino acid
metabolism is an efficacious way to improve the response to anti-PD-1/PD-L1 treatment. Targeting these
metabolic pathways proves to be challenging because, unlike the immunosuppressive metabolites that have
been discussed, amino acids are beneficial for both T cells and tumor cells. Therefore, therapeutic strategies
have to promote amino acid supplementation in T cells but restriction in tumor cells, which is no easy feat.
Despite these challenges, researchers have made great strides in pre-clinical settings towards identifying
how to alter amino acid metabolism in a way that impedes ICB resistance.

LIPID METABOLISM
The TIME is enriched with various lipid classes [205-207] , which is in contrast to other metabolites that are
predominantly depleted. Lipids are ubiquitously important for structural support, energy supply, and
signaling, making them essential for the malignant properties of tumors and for the proper function of anti-
tumor immune cells. Specifically, cholesterol is indispensable for cell membrane integrity and facilitating
cell-to-cell and intracellular signaling, while fatty acids (FAs) are the most abundant lipid intermediate, so
they are more readily detectable and their role in cancer biology is better understood. Therefore, this section
will highlight how tumor-mediated cholesterol and FA dysregulation within the TIME affects CD8 T cell
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function and anti-PD-1/PD-L1 resistance.

Cholesterol
Cholesterol serves as an important component in cellular membranes and regulates membrane fluidity and
cell signaling through the formation of lipid rafts [Figure 3]. Moreover, cholesterol is a precursor for
[208]
steroid hormones, bile acids, and vitamin D . Intracellular cholesterol levels are maintained through
[208]
biosynthesis via the mevalonate pathway, which converts acetyl-CoA to cholesterol through a series of
enzymatic reactions. Additionally, cholesterol is imported as low-density lipoproteins, which are small lipid-
enclosed particles that facilitate the systemic transport and cellular import of cholesterol . On the other
[209]
hand, cholesterol is exported through ATP-binding cassette transporters . Excess intracellular free
[210]
cholesterol is converted to cholesteryl esters and stored in lipid droplets, which promote oncogenic
signaling and cancer growth .
[211]