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Page 624 Laubach et al. Cancer Drug Resist 2023;6:611-41 https://dx.doi.org/10.20517/cdr.2023.60

of function, are associated with resistance to anti-PD-1 treatment [186-188] . Building on this, one group found
that STK11-mutated lung adenocarcinomas from both patient samples and cancer cell lines exhibited
increased glutamate production, so they hypothesized that targeting glutaminase would be a viable way to
[189]
overcome resistance to anti-PD-1 treatment . However, they found that using a non-tumor cell-specific
glutaminase inhibitor in combination with anti-PD-1 severely impeded CD8 T cell clonal expansion and
+
+
[189]
anti-tumor functions, and anti-PD-1 efficacy was dependent on intact CD8 T cell glutaminase activity .
These data demonstrate a promising future for targeting glutamine metabolism to bolster CD8 T cell
+
effector function and combat ICB resistance. However, it also highlights the importance of finding ways to
specifically target malignant cells due to the highly conserved nature of these metabolic pathways.

Methionine
Methionine is an essential amino acid that is involved in a variety of metabolic pathways, such as
methylation reactions, homocysteine synthesis, and the folate pathway [Figure 2]. This metabolite also
cooperates with arginine and glutamine to promote polyamine and glutathione synthesis, respectively . In
[190]
the methionine pathway, methionine is converted to S-adenosyl methionine (SAM), which is critical for the
methylation of histones, DNA, RNA, proteins, and various metabolites . The loss of a methyl group
[191]
converts SAM to S-adenosyl homocysteine (SAH), and subsequently homocysteine, which is ultimately
[192]
metabolized to glutathione . Methionine regeneration is supported by the metabolism of SAM through
the salvage pathway and through the re-methylation of homocysteine via intermediates in the folate
[192]
[193]
pathway .
The role of methionine in malignant transformation and growth is not as well-studied as other metabolites,
but its wide consumption in cancer cells suggests its importance [194,195] . In tumor-initiating cells, exogenous
methionine is consumed at extreme rates, leading to pro-tumorigenic epigenetic modifications through
methionine adenosyltransferase 2A (MAT2A), which metabolizes methionine to SAM to promote histone
methylation . In the presence of methionine, malignant cells activate c-MYC, leading to increased
[196]
MAT2A activity and tumorigenic genome modifications . On the other hand, tumor overexpression of
[197]
nicotinamide N-methyltransferase (NNMT), which converts SAM to NAD and 1-Methylnicotinamide,
+
leads to increased NAD levels, hypomethylation, and tumor progression , highlighting that altered
[198]
+
methionine metabolism can drive oncogenesis in multiple ways.
In T cells, proper metabolic regulation of methionine and its derivatives is necessary for epigenetic
reprogramming during activation and differentiation , as evidenced by increased expression of
[199]
methionine transporters during antigen recognition . However, dysregulated methionine metabolism by
[175]
tumor cells alters the abundance of SAM and 5-methylthioadenosine (MTA) , both of which drive the
[200]
[201]
methionine salvage pathway . Increased abundance of SAM and MTA within the TIME are associated
with T cell exhaustion and expression of inhibitory checkpoint markers . These two metabolites decrease
[200]
+
chromatin accessibility in CD8 T cells for genes involved in TCR signaling, lymphocyte proliferation and
differentiation, and increase the accessibility of PD-1 . Together, these data indicate that tumor-derived
[200]
alterations in methionine metabolism have a substantial impact on the anti-tumor immune functions of
CD8 T cells, but much remains to be discovered.
+
Despite the limited studies in this field, two recent reports demonstrate that restricting tumor methionine
+
increases CD8 T cell effector functions and overcomes resistance to anti-PD-1/PD-L1 treatment. The first
study shows that dietary restriction of methionine reduces SAM levels in murine colorectal carcinoma
[202]
tumors . Mechanistically, SAM controls the expression of immune inhibitory markers PD-L1 and VISTA