TIL therapy in relapsed/refractory neuroblastoma: A translational roadmap from immunobiology to early-phase trials

Relapsed or refractory neuroblastoma (R/R NB) is one of the most challenging pediatric cancers, with long-term survival rates below 20%. Both standard chemotherapy and single-target immune cell therapies are associated with significant limitations. Chemotherapy is unable to clear minimal residual disease in the majority of cases, and engineered cell therapies lose efficacy when tumors drop the target antigen because of intratumoral heterogeneity. Thus, tumor-infiltrating lymphocyte (TIL) therapy offers an alternative approach. TILs are polyclonal and have previously engaged with the tumor, so they can recognize a broad spectrum of patient-specific antigens and are less likely to be compromised by the loss of a single antigen. Nevertheless, early efforts to evaluate TIL therapy in R/R NB have encountered important challenges. The primary obstacles include unsuccessful TIL manufacturing, immunosuppressive tumor microenvironment (TME), and defective antigen presentation due to MYCN-driven loss of MHC class I and impaired interferon signaling. These challenges necessitate novel approaches, such as antigen enrichment or MHC-independent engineering. This review summarizes the results of preclinical research over three decades, categorizing studies into three major periods with distinctive determinants of TIL therapy efficacy in NB. Key clinical studies are also summarized to inform the development, safety, and feasibility of TIL therapy in pediatric NB patients. Finally, a translational roadmap is proposed that integrates γδ TIL enrichment, cell engineering, TME modification, and biomarker-driven patient selection to guide early-phase clinical trials in R/R NB.