Neuroblastoma develops from immature nerve cells and is most commonly diagnosed in children under the age of five. In advanced stages of the disease, despite the use of chemotherapy, radiation therapy, and bone marrow transplantation, the survival rate is around 60%. In cases of relapse, the prognosis is usually poor. Researchers from China have created a cellular map of neuroblastoma and identified new approaches for more effective treatment of this disease.

Immunotherapy and the GD2 Target

In recent years, the main focus has been on immunotherapy based on the use of antibodies targeting the GD2 molecule, which is found on the surface of neuroblastoma cells. Such antibodies, for example those used in therapy with naxitamab, attract immune system killer cells—NK cells and T lymphocytes—to the tumor. However, in about 40% of patients, the tumor does not respond to treatment or becomes resistant.

Cellular Mapping and Signaling Pathways

During the study, tumor samples from 21 children with various stages of neuroblastoma were analyzed, including tissues after chemotherapy and combined treatment with naxitamab. For each cell, active genes were identified, allowing the creation of a detailed cellular atlas of the tumor and its microenvironment.

Comparing tumor cells from high-risk and low-risk cases revealed activation of the NRG3-ERBB4 signaling pathway in neuroblastomas. The tumor releases the NRG3 molecule, and its cells have the ERBB4 receptor on their surface, which responds to this signal. When naxitamab is added to chemotherapy, the activity of this pathway increases, accompanied by greater infiltration of killer cells into the tumor. Thus, the drug not only attacks the tumor via GD2 but also triggers internal signals that increase its vulnerability to the immune system.

Impact on Metabolism and Immune Response

The NRG3-ERBB4 signaling pathway also affects the metabolism of cancer cells, particularly the metabolism of gangliosides—fatty sugars in the cell membrane, including GD2. Activation of this pathway suppresses the synthesis of long-chain gangliosides and alters the composition of ceramides, which helps initiate mechanisms that destroy cancer cells in response to chemotherapy or radiation. As a result, the number of immunosuppressive molecules in the tumor decreases, and the cells become more attractive to T-killer cells.

Experimental Confirmation and New Therapeutic Directions

Experiments on cell lines and mice with transplanted human tumors confirmed that increasing ERBB4 levels in neuroblastoma cells enhances treatment effectiveness. It was also discovered that in resistant tumors, another immune checkpoint is activated—the TIGIT receptor, which is present on some T cells and NK cells. This opens up the possibility for combination therapy that pairs naxitamab with TIGIT blockade.

Outlook

The study involved a small group of patients (21 people, five of whom received combination therapy), but the data obtained point to promising directions in the treatment of neuroblastoma.