APRIL 28, 2025, NEW YORK - A Ludwig Cancer Research study has identified a specific mode of fat uptake by immune cells within tumors that serves as a metabolic checkpoint against anti-cancer immune responses. Harnessing that insight, researchers led by Ludwig Lausanne's Ping-Chih Ho and Yi-Ru Yu-along with Sheue-Fen Tzeng and Chin-Hsien Tsai, former post-docs in the Ho lab who now lead their own labs at Taipei Medical University in Taiwan-have developed a humanized antibody to dismantle that barrier as a potential cancer immunotherapy.
This antibody, PLT012, binds and blocks the activity of CD36, a transporter of lipids that is expressed by immune cells in fat-enriched tumor microenvironments (TMEs). As Ho, Yu and colleagues report in the current issue of Cancer Discovery, PLT012 undermines the metabolic checkpoint mediated by CD36 to restore anti-tumor immunity in mouse models of hepatocellular carcinoma (HCC) as well as liver metastases of colon cancer.
"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.
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.
"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."
