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Laubach et al. Cancer Drug Resist 2023;6:611-41 https://dx.doi.org/10.20517/cdr.2023.60 Page 629

rely heavily on exogenous FAs to sustain their increased rate of FAO [254-257] . In this regard, increased FA
+
abundance within the TIME hinders CD8 T cell function, while benefiting malignant and
immunosuppressive cells.

FAs are the building blocks for a variety of bioactive lipids, which are involved in signaling pathways.
Tumor cells, and to a lesser extent CAFs , secrete the enzyme autotaxin (ATX) that converts ubiquitously
[258]
[259]
available lysophosphatidylcholine (LPC) to the bioactive lipid lysophosphatidic acid (LPA) . LPA
modulates numerous signaling pathways through lysophosphatidic acid receptors 1-6 (LPAR1-6), which are
[259]
present on a variety of cell types . In malignant cells, the ATX/LPA axis also functions in an autocrine
manner by promoting oncogenic signaling through LPAR1 . On CD8 T cells, tumor-derived LPA binds
+
[260]
[260]
to LPAR6 and prevents tumor infiltration by inhibiting migration . LPA also signals through LPAR5 on
CD8 T cells to induce cytoskeletal dysfunction, immunological synapse malformation, and impaired
+
cytokine secretion and intracellular calcium release [261-263] . LPAR5 signaling on CD8 T cells also induces an
+
exhausted-like state by promoting metabolic stress through ROS production and ultimately impairing
antigen-specific killing . The recent development of a first-in-class ATX inhibitor demonstrated tumor
[264]
growth inhibition in mouse models of breast cancer [265,266] . The safety of this compound was tested in Phase I
clinical trials in 2021, where the drug was well-tolerated with no significant clinically adverse effects .
[266]
These promising results demonstrate the previously unexplored capacity to target ATX in solid tumors,
with the future potential to combine this treatment with pre-existing ICB therapies.
There is very limited research on targeting FA metabolism in combination with anti-PD-1/PD-L1 therapy,
but more evidence is emerging that supports this approach to overcome ICB resistance. Bioinformatics
methods have identified that FASN expression in patients with bladder cancer, melanoma, and non-small
cell lung carcinoma is linked to immune infiltration and ICB response [267,268] . Interestingly, ICB is more
efficacious in obese patients with melanoma compared to non-obese patients [252,269-272] . While this may seem
+
contradictory, obesity drives PD-1 expression on CD8 T cells, thus eliciting a more robust response. On the
other hand, CD8 TILs in pancreatic adenocarcinoma exhibit increased expression of checkpoint inhibitors,
+
but ICB therapy largely fails [273-275] . The variability in ICB response between cancer types prompts the need
for a deeper understanding of the mechanisms that contribute to resistance. To further complicate things,
under hypoxic and hypoglycemic conditions, pharmacologically enhancing FA catabolism in CD8 T cells
+
[206]
promotes effector function . Moreover, anti-PD-1 treatment, in combination with increased FA
catabolism, synergistically reduced the volume of murine melanoma tumors and promoted anti-
[206]
+
tumorigenic metabolic reprogramming in CD8 T cells . These data suggest that under stressful
conditions, i.e., oxygen and glucose depletion, increased FAO is required for CD8 T cell function, but this
+
contradicts other studies that demonstrate a shift towards FAO promotes exhaustion.
Together, these research efforts have laid the groundwork to further characterize the intricate relationship
+
between tumor-mediated cholesterol and FA metabolism and CD8 T cell function within the TIME. To
date, it is not clear whether inhibiting cholesterol or FA metabolism is a viable treatment option to improve
response to anti-PD-1/PD-L1 therapies. As new data emerges, researchers will have a better understanding
of the tumor-specific cholesterol and FA metabolic programs that are exploited by cancer cells and if these
can be targeted to prevent ICB resistance.

CONCLUSION
While ICB therapies have been an imperative advancement in cancer treatment, a majority of patients
exhibit resistance, prompting the need for researchers to identify and target these resistance mechanisms.
This review has provided a multitude of examples wherein tumor-intrinsic alterations to energy, amino