Metabolomic reprogramming of the tumor microenvironment by dual arginase inhibitor OATD-02 boosts anticancer immunity
Опубликована: Апрель 1, 2025
Abstract
Metabolic
reprogramming
within
the
tumor
microenvironment
(TME)
plays
a
central
role
in
cancer
progression
and
immune
evasion,
with
L-arginine
metabolism
emerging
as
key
regulatory
axis.
Arginase
overexpression
depletes
intratumoral
L-arginine,
thus
suppressing
T-cell
proliferation
while
fuelling
growth
through
polyamine
biosynthesis.
OATD-02,
novel
dual
arginase
(ARG1/ARG2)
inhibitor,
reprograms
by
restoring
availability
reducing
levels
of
polyamines,
thereby
shifting
TME
toward
more
immunostimulatory
state.
Unlike
ARG1-selective
inhibitors
limited
intracellular
uptake,
OATD-02
effectively
inhibits
both
extracellular
arginases,
addressing
major
limitation
first-generation
inhibitors.
To
visualize
pharmacodynamic
effects
dosing
mice
spatial
resolution,
we
employed
MALDI
mass
spectrometry
imaging
(MALDI-MSI),
enabling
direct
mapping
metabolic
changes
tissues.
In
preclinical
models,
treatment
led
to
widespread
accumulation
concomitant
depletion
polyamines
resulted
shifts
that
correlated
increased
cell
infiltration
an
improved
response
checkpoint
blockade.
These
findings
underscore
inhibition
reshaping
overcoming
suppression
fitness
cells
fight
cancer.
The
caused
significantly
enhanced
antitumor
responses,
tumors,
expansion
CD8⁺
T
draining
lymph
nodes,
systemic
upregulation
activation
markers.
translated
into
substantial
survival
benefit
CT26
model,
particularly
when
combined
anti-PD-1
therapy,
where
blockade
efficacy
relieving
constraints
affecting
tumor-infiltrating
lymphocytes.
By
leveraging
unique
capabilities
MALDI-MSI,
this
study
provides
high-resolution
insights
mechanism
action
reinforcing
its
potential
next-generation
metabolic-immunotherapeutic
agent.
observed
reprogramming,
coupled
prolonged
survival,
supports
clinical
development
promising
strategy
for
enhancing
immunotherapy
efficacy.
is
currently
undergoing
evaluation
phase
I/II
trial
(NCT05759923),
which
will
further
elucidate
safety
therapeutic
impact.
highlight
arginase-targeted
therapies
value
MALDI-MSI
powerful
tool
tracking
responses
therapy.
Язык: Английский
Cell competition as an emerging mechanism and therapeutic target in cancer
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease,
Год журнала:
2025,
Номер
1871(5), С. 167769 - 167769
Опубликована: Март 5, 2025
Язык: Английский
ASPiring metabolic-immunotherapy by ASParaginase.
PubMed,
Год журнала:
2025,
Номер
unknown
Опубликована: Март 5, 2025