Identifying immunosuppressive factors in the neuroblastoma TME to boost CAR-T efficacy
Strijker JGM, Pascual-Pasto G, Grothusen GP, et al. Blocking MIF Secretion Enhances CAR T-Cell Efficacy Against Neuroblastoma. European Journal of Cancer. 2025; 218 (doi: 10.1016/j.ejca.2025.115263).
Scientists are learning more about how T cell trogocytosis — the exchange of membrane-associated proteins between cells — is regulated, knowledge that could potentially unlock novel pathways for chimeric antigen receptor (CAR) T-cell therapy. Researchers now know tImmunosuppressive tumor microenvironments (TMEs) attenuate the effects of chimeric antigen receptor (CAR) T-cell therapy in solid tumors, but scientists believe this challenge can be overcome by identifying and targeting secreted factors that contribute to the unfavorable conditions. In the case of neuroblastoma, a pediatric extracranial solid cancer, a multi-omics approach was employed to flag tumor-derived soluble factors that potentially thwart CAR-T efficacy. Of particular interest was Macrophage Migration Inhibitory Factor (MIF), which researchers found to be heavily secreted in the TME, where it blocked CAR T-cell activation and killing capacity. Protein degrader (PROTAC) technology degraded MIF and significantly curtailed tumoral secretion which, in turn, markedly enhanced CAR T-cell efficacy. The findings suggest that selective targeting of MIF may represent a novel pathway for boosting the efficacy of CAR T-cell therapy in neuroblastoma, and possibly other solid tumors, and improving patient outcomes. hat cell-cell contact is critical for trogocytosis to take place; however, the likelihood of a specific protein undergoing this process ultimately is dictated by its transmembrane domain. When trogocytosis of CARs does occur, investigators say anti-tumor immunity is effectively transferred to recipient T cells, which are then able to up-regulate proteins tied to cytotoxic response and eradication of tumor cells. Trogocytosis has the potential to arrest immune response as well as boost it; therefore, identifying techniques for modulating this process in CAR T-cells would be beneficial.