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Laubach et al. Cancer Drug Resist 2023;6:611-41 https://dx.doi.org/10.20517/cdr.2023.60 Page 627

regulates cholesterol levels by facilitating the degradation of low-density lipoprotein receptors
(LDLR) [221-224] , which imports low-density lipoprotein cholesterol. Tumor-secreted PCSK9 promotes
+
[225]
intratumoral accumulation of cholesterol , prevents LDLR and TCR recycling in CD8 TILs , and
[226]
[227]
inhibits MCH-1 recycling on tumor cells , leading to immune evasion in multiple ways. Further, several
reports demonstrate that intratumoral cholesterol accumulation promotes PD-L1 expression [228-231] , thereby
contributing to immune evasion. Mechanistically, cholesterol binds to the transmembrane domain of
PD-L1 to stabilize cell surface expression . Cholesterol-derived metabolites produced by malignant cells
[231]
also dictate anti-tumor response. For example, cholesterol sulfate creates a chemical barrier within the
TIME to prevent CD8 T cell infiltration . Moreover, cholesterol sulfate-producing tumors are more
+
[232]
resistant to ICB therapy than tumors that do not produce this metabolite, demonstrating that targeting
[232]
tumor-intrinsic cholesterol metabolism could enhance ICB outcomes.
In addition to cholesterol biochemical pathways regulating CD8 T cell function, mechanical forces driven
+
by altered cholesterol levels within tumor cells also influence anti-tumor immune response. Cancer cells
accumulate cholesterol within the cell membrane, leading to increased membrane fluidity, or “cell
[219]
softening” . This phenomenon is associated with cancer development and progression because cancer cell
softening impairs the cytotoxic effects of T cells, leading to immune escape . By reversing these effects and
[219]
promoting cancer cell stiffening, increased T cell forces and actin accumulation at the immunological
synapse enhance tumor killing . Notably, cancer cell stiffening did not alter TCR signaling or cytokine
[219]
[219]
production, demonstrating that these effects were purely through mechanical forces .
In T cells, maintaining a proper balance between membrane and intracellular cholesterol levels is important
for development, activation, and effector functions. Cholesterol in the cell membrane is essential for the
intricate formation of lipid rafts which regulate TCR signaling . In TILs, several studies report that the
[233]
allocation of cholesterol towards cell membrane formation instead of storage as cholesterol esters promotes
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anti-tumor activities. Pharmacologic inhibition in tumor cells and CD8 T cells of acyl-CoA cholesterol
acyltransferase 1 (ACAT1), which promotes cholesterol esterification, inhibits cancer cell growth .
[234]
Similarly, another group found that RORa, a nuclear hormone receptor, promotes CD8 T cell membrane
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cholesterol accumulation by inhibiting cholesterol esterification, thus enhancing anti-tumor functions .
[235]
+
On the other hand, intracellular cholesterol accumulation in CD8 T cells due to cholesterol enrichment in
the TIME leads to endoplasmic reticulum (ER) stress, which causes T cell exhaustion and increased
expression of immune checkpoint markers . Mechanistically, ER stress promotes upregulation of the ER
[207]
stress sensing protein XBP1, which drives the expression of immune inhibitory markers, namely PD-1 and
2B4 . As a result, inhibiting XBP1 or reducing cholesterol in CD8 T cells or the TIME boosts the anti-
[207]
+
tumor functions of CD8 T cells . These studies demonstrate that shifting cholesterol away from
[207]
+
intracellular stores towards membrane formation in T cells might be an effective therapeutic strategy to
diminish resistance to ICB therapy.
+
Given the profound effect of tumor-derived cholesterol on CD8 T cell function, it is no surprise that
targeting this altered metabolic pathway inhibits resistance to anti-PD-1 treatment. Building on the idea that
allocating cholesterol towards cellular membranes in CD8 T cells is beneficial for the anti-tumor response,
+
researchers found that pharmacologic inhibition of ACAT1 in combination with anti-PD-1 treatment
synergistically reduced the growth of mouse melanoma tumors . Further, slight anti-tumor effects were
[236]
observed in four mouse tumor models following genetic ablation of PCSK9, but combination of genetic or
pharmacologic inhibition of PCSK9 with anti-PD-1 resulted in robust synergistic effects to increase MHC-I
[227]
expression and survival and reduce growth of murine melanoma and colorectal carcinoma tumors .
Another emerging target is squalene epoxidase (SQLE), which catalyzes one of the rate-limiting steps in