A novel spliceosome inhibitor triggers anti-tumor CD4+ and CD8+ T cell responses in murine models of pediatric-relevant cancer.
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Immunotherapy has been proved to have a high potential to change the outcomes of patients with advanced cancer. However, the efficacy of immune checkpoint inhibitors in most classical pediatric cancers remains limited, underscoring the need for other novel immunomodulatory strategies, such as small-molecule agents, either synthetically derived or isolated from natural sources, which can modulate intracellular immune pathways. Among these, spliceosome inhibitors have emerged as a promising class of compounds capable of reshaping the tumor antigenic landscape. We developed a new generation of spliceosome-targeting molecules that interfere with mRNA processing, enhance major histocompatibility complex class I (MHC-I) and MHC-II expression in tumor cell, and potentiate T cell-mediated immune responses. The new splicing inhibitor BL828 inhibited spliceosome function, upregulated surface MHC-I and MHC-II expression, and induced hallmarks associated with immunogenic cell death in vitro. In neuroblastoma-bearing mice, BL828 treatment significantly delayed tumor growth in an immune-dependent manner, modulated the tumor microenvironment with enhanced activation of antigen-presenting cells, and promoted a robust CD8+ T cell and CD4+ cytotoxic-like T cell response against murine pediatric neuroblastoma cancers. These findings support splicing inhibition as a strategy to enhance antigen presentation and anti-tumor immunity in murine models of pediatric-relevant cancers, supporting further evaluation of BL828 as a therapeutic candidate.