SLIDE 2
1. T-cells Introduction
a) T-cells as defense mechanism as right fuels to activate, multiply, kill cancer
cells
b) Manipulating metabolic checkpoints, to improve cancer immunotherapies
c) Immunometabolism examines how intracellular metabolic pathways govern
internal function. In T lymphocytes, metabolic reprogramming is tightly
coupled to activation:
i. antigen recognition via the T cell receptor and costimulatory signals
trigger transcriptional and post-translational programs (mTOR, HIF-1α,
c-Myc) that upregulate glucose uptake, glycolysis, and biosynthetic
pathways to support rapid proliferation and effector cytokine production.
ii. Conversely, memory and regulatory T cell subsets preferentially utilize
oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO),
reflecting divergent bioenergetic and biosynthetic demands
iii. The tumour microenvironment (TME) perturbs this balance via nutrient
depletion (glucose, certain amino acids), hypoxia, acidification (lactate
accumulation), and immunosuppressive metabolites (adenosine,
kynurenine). These conditions impose metabolic checkpoints: specific
transporters (e.g., GLUT1, ASCT2/SLC1A5), enzymes (HK2, LDHA,
IDO), and metabolite sensors that determine whether T cells achieve
sufficient ATP, reducing power, and biosynthetic precursors. Failure to
pass these checkpoints leads to impaired proliferation, diminished
effector function, expression of exhaustion markers (PD-1, TIM-3), and
reduced antitumor activity.
2. Targeting metabolic checkpoints
a) Reprogramming T cell function. Strategies include modulating nutrient
availability, inhibiting tumour metabolic pathways that create hostile niches,
or enhancing T cell metabolic flexibility (e.g., promoting mitochondrial
fitness). The field integrates enzymology, transporter biology, signal
transduction, and translational immunotherapy to translate metabolic control
into actionable interventions for cancer.
b) T cell metabolism encompasses interconnected pathways that supply ATP,
biosynthetic precursors.
i. Necessary for proliferation and effector function.
ii. Naïve T cells primarily rely on mitochondrial OXPHOS and basal
glycolysis for homeostatic maintenance.
iii. Upon activation, T cells undergo rapid metabolic reprogramming
characterized by increased glucose uptake (GLUT1 induction), enhanced
aerobic glycolysis (Warburg-like phenotype)
SLIDE 3
3. Signalling Pathways
a) Glycolysis in activated effector T cells supplies ATP and glycolytic
intermediates for nucleotide, lipid, and amino-acid synthesis
i. mTORC1-dependent signaling and HIF-1α-mediated transcription of
effector genes— critical for maintaining redox balance during rapid
proliferation.
ii. OXPHOS and mitochondrial respiration remain important, particularly
for sustained ATP production and for memory T cell differentiation,
which is associated with increased mitochondrial mass
b) Metabolic sensors (AMPK, mTOR) and transcription factors (c-Myc, HIF-
1α, PGC-1α) integrate nutrient and energy signals to coordinate metabolic
pathway allocation.
i. Metabolic checkpoints denotes molecular nodes—transporters,
metabolic enzymes, and metabolite-sensitive signaling molecules—
thereby regulate immune cell activation and differentiation.
ii. Tumor cells impose metabolic competition and create suppressive
metabolites; (2) specific transporters and enzymes in T cells serve as
critical determinants of effector competence
SLIDE 4
4. T-cell Immunometabolism
a) Tumour metabolic reprogramming includes enhanced glycolysis (the
Warburg effect), glutamine addiction, and altered lipid metabolism. These
shifts deplete extracellular glucose and amino acids and increase
concentrations of lactate, adenosine, and kynurenine, each of which
suppresses T cell receptor signaling, cytokine production, and proliferation.
For instance, lactate and associated acidification impair NFAT translocation
and IFN-γ production, while adenosine acting via A2A receptors elevates
intracellular cAMP and inhibits T cell activation.
TLS formation: Cellular Players: Lymphoid tissue inducer (LTi) cells, lymphoid tissue
organizer (LTo) cells, dendritic cells (DCs), follicular helper T (Tfh) cells, germinal
center (GC) B cells, CD8⁺ T cells, and high endothelial venule (HEV) endothelial cells.
Molecular Drivers: Cytokines (IL-6/17, TNF-α, IFNs), chemokines (CXCL12/CXCL13,
CCL19/21), the STING pathway (cGAS-cGAMP-STING-IRF3), and LT/LTβR/TNFR1
signaling.
Metabolic Cues: Reprogramming of glucose, lipid, amino acid, and vitamin
metabolism to support immune cell activation, recruitment, and structural
organization.
b)