In a transformative leap for cancer immunotherapy, researchers at Ludwig Cancer Research, led by Ping-Chih Ho and Yi-Ru Yu from Ludwig Lausanne, have unveiled a novel therapeutic antibody that targets a metabolic vulnerability within tumors. Their groundbreaking study, recently published in Cancer Discovery, elucidates a unique mechanism of fat uptake by immune cells in tumor microenvironments. This newly discovered pathway acts as a metabolic checkpoint, suppressing the immune system’s ability to combat cancer. By neutralizing this checkpoint through a humanized antibody named PLT012, the team offers promising prospects for effective immunotherapy against notoriously resistant tumors such as hepatocellular carcinoma and liver metastases from colon cancer.
Traditional immune checkpoint inhibitors, like PD-1 and PD-L1 blockers, have revolutionized cancer treatment by "releasing the brakes" on immune cells, particularly cytotoxic CD8+ T cells. However, a significant subset of cancers creates microenvironments that are hostile to immune attack, limiting the efficacy of these treatments. The study led by Ho and Yu delves into these metabolic complexities, highlighting how the accumulation and metabolism of lipids within the tumor microenvironment (TME) serve as a covert immunosuppressive strategy deployed by cancers. At the heart of this mechanism is CD36, a lipid transporter upregulated on several immune cell subsets within fat-rich TMEs.
CD36 mediates the uptake of fatty acids and cholesterol, molecules abundant in these hostile microenvironments characterized by acidity and hypoxia. This influx of lipids alters immune cell functions in a profoundly deleterious manner. Immunosuppressive cells, including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), harness these lipids to enhance their tumor-protective abilities. Conversely, anti-tumor immune cells such as CD8+ T lymphocytes endure metabolic dysfunction and ferroptosis, a lipid peroxidation-driven cell death, severely impairing their cytotoxic potential.
Recognizing CD36 as a critical metabolic checkpoint—distinct from canonical protein-based immune checkpoints—the researchers crafted PLT012, a monoclonal antibody designed to block CD36’s fatty acid binding sites. In preclinical mouse models reflecting human liver cancer and metastatic colon cancer, PLT012 robustly restored anti-tumor immunity. The therapy effectively diminished lipid accumulation in suppressive immune cells, simultaneously reviving exhausted CD8+ T cells and shifting the tumor immune landscape from immunosuppressive to immunostimulatory.
Crucially, the antibody displayed potent synergy with existing checkpoint inhibitors, suggesting that targeting metabolic checkpoints can overcome resistance mechanisms that have plagued standard immunotherapies. “Tumors with lipid-rich microenvironments represent a formidable challenge, often evading conventional treatments through intricate metabolic and immunological barriers,” explained Ho during his presentation at the 2025 AACR Annual Meeting. “Our approach doesn’t just lift the brakes; it reprograms the immune system’s metabolic machinery, offering a dual mode of attack.”
Cellular analysis of tumor samples from hepatocellular carcinoma patients further validated the antibody’s potential translational relevance. PLT012 reshapes immune cell populations, reducing the presence and suppressive function of Tregs and MDSCs while rejuvenating effector T cells capable of tumor eradication. This metabolic modulation suggests that therapies that target lipid handling pathways may have broad applicability beyond liver cancers, extending to a variety of tumors exhibiting lipid-enriched microenvironments.
Safety assessment is paramount when targeting broadly expressed molecules like CD36, which is present not only on immune cells but also on many other tissues. Encouragingly, studies conducted in non-human primates and mouse models demonstrated that PLT012 does not precipitate systemic autoimmune toxicity. This safety profile underscores the antibody’s promise for clinical development, addressing a major hurdle that often limits the therapeutic targeting of metabolic regulators.
The lipid-induced dysfunction of CD8+ T cells involves ferroptosis, a form of programmed cell death driven by iron-dependent lipid peroxidation. By blocking CD36, PLT012 prevents excessive lipid uptake that would otherwise push these cytotoxic cells towards ferroptotic death. This protective effect preserves the vitality and function of the immune system’s principal tumor-killing agents, reinforcing robust and sustained anti-cancer responses.
From a therapeutic development perspective, PLT012’s designation as an orphan drug by the U.S. Food and Drug Administration reflects recognition of its innovative mechanism and potential to fulfill unmet clinical needs, especially for hard-to-treat liver cancers. The antibody is currently poised for clinical evaluation through a spin-off company, marking a new chapter in targeting metabolic dimensions of cancer immunity.
This study also deepens scientific understanding of cancer’s multifaceted immune evasion strategies. Cancers do not merely evade detection by masking themselves or recruiting suppressor cells; they reshape their microenvironment at a metabolic level, manipulating fatty acid fluxes to their advantage. Targeting such metabolic checkpoints might redefine not only how immunotherapies are designed but also how combination regimens are optimized to overcome complex tumor defenses.
In summary, the discovery and development of PLT012 by Ho, Yu, and their colleagues offer a transformative paradigm in cancer immunotherapy. By dismantling the lipid-mediated metabolic checkpoint orchestrated by CD36, this therapy reinvigorates anti-tumor immunity, potentially addressing a spectrum of cancers that have thus far resisted immunologic eradication. These findings herald a new era where modulation of tumor metabolism becomes an integral pillar of immune-based cancer treatment strategies.
Subject of Research:
Lipid-mediated metabolic checkpoints in tumor microenvironments and the development of PLT012, a humanized CD36-blocking antibody for cancer immunotherapy.
Article Title:
PLT012, a Humanized CD36-Blocking Antibody, Reverses Metabolic Immunosuppression in Fat-Enriched Tumor Microenvironments.
News Publication Date:
April 28, 2025.
Image Credits:
Ludwig Cancer Research
Keywords:
Cancer immunotherapy, lipid metabolism, metabolic immune checkpoint, CD36, PLT012 antibody, tumor microenvironment, hepatocellular carcinoma, immune suppression, ferroptosis, regulatory T cells, myeloid-derived suppressor cells, checkpoint blockade resistance.
