This study developed a novel humanized anti-CD36 antibody, PLT012, which effectively blocks CD36-mediated lipid uptake, significantly enhances anti-tumor immune responses, and demonstrates robust anti-tumor activity across multiple mouse models and high-fat diet conditions. It provides a new immunotherapeutic strategy for liver cancer and metastatic liver cancer.
Literature Overview
This article, "PLT012, a humanized CD36-blocking antibody, is effective for unleashing anti-tumor immunity against liver cancer and liver metastasis," published in *Cancer Discovery*, reviews lipid metabolism reprogramming mechanisms in tumor microenvironments (TME) and therapeutic potential of CD36-targeting immunomodulation in liver cancer and metastasis models. Through multi-omics analysis and animal experiments, the research team revealed PLT012's ability to restore immune surveillance in immune checkpoint inhibitor-resistant models.
Background Knowledge
Liver cancer ranks among the most lethal malignancies globally, with its immune therapy resistance posing significant clinical challenges. CD36, a fatty acid transport protein, has been shown to regulate T cell and regulatory T cell (Treg) functions within the TME. Treg cells exhibit high CD36 expression in liver cancer microenvironments, where lipid uptake enhances their immunosuppressive functions, while CD8+ T cells undergo ferroptosis due to lipid overload, impairing anti-tumor immunity. Targeting CD36 with antibodies may thus reshape the TME by modulating metabolic pathways in Treg and CD8+ T cells, enhancing anti-tumor immune responses. The study presents PLT012, a potent cross-species humanized IgG4 antibody, validated for safety and efficacy in mouse and non-human primate models, offering a new molecular target for liver cancer immunotherapy.
Research Methods and Experiments
The research team employed gene-edited mouse models, flow cytometry, single-cell RNA sequencing, and cryo-electron microscopy (Cryo-EM) structural analysis to evaluate PLT012's specificity for CD36 binding pockets, its inhibition of lipid uptake in Treg and CD8+ T cells, and its capacity to reprogram tumor microenvironments. High-fat diet models and immune checkpoint inhibitor-resistant models were used to assess anti-tumor activity under diverse metabolic stresses, while peripheral blood and tissue samples were analyzed for pharmacokinetics and safety.
Key Conclusions and Perspectives
Research Significance and Prospects
The study provides preclinical evidence for CD36-targeted immunotherapy, demonstrating PLT012's robust anti-tumor activity in cold tumor and immune checkpoint inhibitor-resistant models. Future research should explore PLT012 combination therapies with PD-1/PD-L1 or VEGF inhibitors to improve immune response rates in liver cancer patients. Additionally, this work offers novel therapeutic insights for other cancers where lipid metabolism regulates immune cell function.
Conclusion
This study systematically evaluated the anti-tumor immunomodulatory effects of anti-CD36 antibody PLT012 in liver cancer and metastasis models. Through multiple experimental models and molecular mechanism analyses, the research team elucidated CD36's critical role in lipid metabolism of Treg and CD8+ T cells, and confirmed PLT012's ability to reprogram immune microenvironments and enhance anti-tumor responses across diverse immune status tumors. The antibody exhibited excellent safety profiles in non-human primates and significantly improved CD8+ T cell function in human liver cancer ex vivo models. Thus, PLT012 represents a promising new targeted antibody for liver cancer immunotherapy, particularly for patients non-responsive to conventional immune checkpoint inhibitors.
