A groundbreaking study by Ludwig Cancer Research has unveiled a unique method through which immune cells within tumors absorb fats, creating a metabolic barrier against anti-cancer immune responses. Researchers, spearheaded by Ping-Chih Ho and Yi-Ru Yu from Ludwig Lausanne, along with collaborators Sheue-Fen Tzeng and Chin-Hsien Tsai, have engineered PLT012, a humanized antibody designed to dismantle this metabolic checkpoint as a novel cancer immunotherapy. This antibody targets CD36, a lipid transporter expressed in fat-rich tumor microenvironments (TMEs). In mouse models of hepatocellular carcinoma (HCC) and colon cancer liver metastases, PLT012 successfully restores anti-tumor immunity by blocking CD36 activity. The researchers also demonstrated its potential in reshaping the immune landscape of tumors isolated from HCC patients, indicating promising therapeutic effects in humans.

CD36 plays a pivotal role in the metabolic reprogramming of the tumor microenvironment. In response to acidic and high-fat conditions, various immune cells increase their expression of CD36, enhancing the import of specific fat molecules and cholesterol. This influx of lipids affects different immune cell types in contrasting ways, often favoring tumor survival. For instance, myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) benefit from these lipids, strengthening their immunosuppressive functions. Meanwhile, macrophages that could potentially eliminate cancer cells are reprogrammed into a pro-tumor state. Conversely, CD8+ T cells, key players in anti-tumor immunity, experience severe dysfunction and programmed cell death known as ferroptosis.

In their study, Ho, Yu, and their team found that PLT012 effectively reverses these adverse effects by inhibiting CD36's ability to bind fatty molecules. Notably, it achieves this without inducing autoimmune reactions in monkeys and mice, despite the widespread presence of CD36 throughout the body. Unlike traditional immune checkpoint inhibitors that falter in metabolically hostile TMEs, PLT012 operates upstream by modulating lipid metabolism, dismantling the tumor's immunosuppressive architecture. By targeting CD36, PLT012 selectively reduces lipid accumulation in Tregs and MDSCs while preserving and restoring effector T cell function, unlocking robust anti-tumor immunity even against traditionally resistant tumor types.

The implications of this research extend beyond liver cancer, as CD36 is widely expressed across multiple tumor types with lipid-rich microenvironments. The U.S. Food and Drug Administration has designated PLT012 as an "orphan drug," and a spin-off company is developing it for clinical trials. This discovery not only introduces a new class of immunotherapeutics but also enhances our understanding of the metabolic barriers cancers employ to evade immune clearance. As such, PLT012 represents a significant advancement in the field of cancer immunotherapy, offering hope for more effective treatments against previously resistant cancers.