Researchers from Ludwig Cancer Research have developed an antibody, PLT012, that targets the lipid transporter CD36 to reverse immune suppression in fat-rich tumor environments, restoring anti-tumor immunity in preclinical models. This antibody shows promise in overcoming resistance to conventional immunotherapies, particularly in liver and colon cancers, and is now being developed for clinical use.
The antibody PLT012 targets the
fat transporter CD36 to restore immune responses in tumors, offering a new and
promising approach to treating immunotherapy-resistant cancers.
A new study from Ludwig Cancer
Research has uncovered a key mechanism by which immune cells within tumors take
up fat, a process that functions as a metabolic checkpoint, suppressing the
body’s anti-cancer immune responses.
Building on this discovery, a research
team led by Ping-Chih Ho and Yi-Ru Yu of Ludwig Lausanne, in collaboration with
Sheue-Fen Tzeng and Chin-Hsien Tsai (former postdoctoral fellows in the Ho lab
and now principal investigators at Taipei Medical University), has developed a
novel antibody to disrupt this checkpoint as a potential cancer immunotherapy.
The antibody, named PLT012, targets
and inhibits CD36, a lipid transporter found on immune cells within fat-rich
tumor microenvironments (TMEs). According to findings published in Cancer Discovery, PLT012 blocks CD36-mediated lipid
uptake, effectively disabling the metabolic checkpoint that impairs immune
function. In preclinical studies, PLT012 restored anti-tumor immunity and
significantly inhibited tumor growth in mouse models of hepatocellular
carcinoma (HCC) and colon cancer liver metastases.
Promising Results in Preclinical Models
“Though checkpoint blockade
immunotherapies have transformed cancer care, they have had limited success
against several major types of tumors, especially those that cultivate highly
immunosuppressive microenvironments,” said Ho, who also presented his team’s
findings on April 28th at the 2025 Annual
Meeting of the American Association for Cancer Research in Chicago. “Our study
demonstrates that PLT012 induces potent anti-tumor responses even in
immunotherapy-resistant liver cancer models and exhibits strong synergy with
checkpoint blockade immunotherapy as well as other standard-of-care treatment
regimens.”
The researchers also show that the
antibody reshapes the immune landscape of tumors isolated from HCC patients,
suggesting it is likely to replicate its therapeutic effects in humans.
Further, they demonstrate via studies conducted in monkeys and mice that,
thanks to its rational design, the antibody has a safety profile that supports
its use as an immunotherapy.
“Taken together, our findings
establish CD36 as a targetable metabolic immune checkpoint and introduce PLT012
as the first of a new and potentially promising class of immunotherapies,” said
Yu.
CD36: A Metabolic Gatekeeper for Immune Suppression
Cancers evolve to sabotage immune
surveillance and attack. They do so in many ways, most famously by expressing
so-called “immune checkpoint” proteins like PD-L1, which tricks CD8+ T cells
tasked with killing cancer cells into “seeing” them as healthy. They also
recruit and nurture immune cells, like regulatory T cells (Tregs) and
myeloid-derived suppressor cells (MDSCs), that inhibit anti-tumor immune
responses. Another way tumors escape immune clearance is by tweaking the
metabolic properties of their microenvironments to induce dysfunction in
attacking immune cells, or to reprogram them from an anti-tumor state into one
in which they support tumor survival and growth.
It is in such machinations that the
lipid transporter CD36 plays a starring role. In response to the acidity and
high fat concentration of the TME, many types of immune cells step up their
expression of the transporter, boosting the import of certain types of fat
molecules and cholesterol. The influx of fat has radically divergent effects on
different species of
immune cells—effects that seem to consistently favor the tumor. MDSCs and Tregs
thrive on the lipid snacks, which bolster their immunosuppressive function.
Macrophages that might gobble up cancer cells and help orchestrate an immune
assault are reprogrammed to flip into a pro-tumor state. Meanwhile, CD8+ T
cells—the chief effectors of anti-tumor immunity—suffer profound dysfunction
and a type of programmed death known as ferroptosis.
Yu, Ho and colleagues show in their
study that PLT012, which blocks CD36’s ability to latch on to fatty molecules,
reverses almost all these effects. And it does so without triggering
potentially toxic autoimmune reactions in monkeys and mice, despite the broad
expression of the transporter throughout the body.
A New Therapeutic Avenue
“Unlike conventional immune checkpoint
inhibitors, which fail in metabolically hostile TMEs, PLT012 acts
upstream—modulating lipid metabolism to dismantle the immunosuppressive
architecture of the tumor,” said Yu. “By targeting CD36, PLT012 selectively
reduces lipid accumulation in Tregs and MDSCs while preserving and restoring
the function of effector T cells in our preclinical studies. This reprogramming
unlocks robust anti-tumor immunity in cancer models, even against tumor types
that have traditionally resisted checkpoint blockade immunotherapies.”
The antibody has received “orphan
drug” designation from the U.S. Food and Drug Administration and is being
developed for clinical evaluation by a spin-off company.
“The implications of this study extend
beyond liver cancer, as CD36 is broadly expressed across multiple tumor types
with lipid-rich microenvironments,” said Ho. “It not only ushers a potentially
new class of immunotherapeutics to the clinic but also deepens our
understanding of the metabolic barriers to immune clearance generally employed
by cancers.”
Reference: “PLT012, a Humanized
CD36-Blocking Antibody, Is Effective for Unleashing Antitumor Immunity Against
Liver Cancer and Liver Metastasis” by Sheue-Fen Tzeng, Yi-Ru Yu, Jaeoh Park,
Janusz von Renesse, Huey-Wen Hsiao, Chen-Hsuan Hsu, Josep Garnica, Jintian
Chen, Lu-Ting Chiu, Jonas Santol, Tse-Yu Chen, Pei-Han Chung, Lana E.
Kandalaft, Patrick Starlinger, Rodney Cheng-En Hsieh, Ming-Chin Yu, Pei-Wen
Hsiao, Santiago J. Carmona, Hung-Kai Chen, Zhen Meng, Yun-Han Lin, Jingying
Zhou, Chin-Hsien Tsai and Ping-Chih Ho, 28 April 2025, Cancer Discovery.
DOI: 10.1158/2159-8290.CD-24-1409
The study was funded by the Ludwig
Institute for Cancer Research.
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