Galectin-3 blockade reprograms the tumor microenvironment and improves CAR T-cell therapy in pediatric cancers

CAR T-cell therapies have revolutionized the treatment of hematological malignancies, yet their efficacy in solid tumors remains limited. Pediatric solid tumors are particularly challenging due to their low mutational burden, scarce T-cell infiltration, and highly immunosuppressive tumor microenvironment (TME). Although CAR T cells can induce initial responses, sustaining durable activity is difficult. To identify mechanisms that could be targeted to enhance CAR T-cell function, we performed scRNA-seq analysis of nearly 100 pediatric tumor samples and characterized the T-cell and myeloid compartments. We found that Galectin-3 (Gal3), an immunosuppressive and protumorigenic molecule, was predominantly expressed by myeloid cells and strongly associated with an M2-like macrophage phenotype. Gal3 expression inversely correlated with overall T-cell infiltration and, more specifically, with the proportion of reactive-like T cells. Spatial imaging confirmed Gal3 protein expression in the TME and showed colocalization with immunosuppressive myeloid of T cell markers Based on these findings, we hypothesized that Gal3 inhibition could synergize with CAR T-cell activity by alleviating myeloid-driven immunosuppression. To deliver Gal3 inhibition directly within the TME, we engineered an “armed” CAR T cell that secretes a protein-based Gal3 inhibitor. Functional characterization is ongoing, and in vivo evaluation in pediatric tumor mouse models is currently in progress. Our results identify Gal3 as a key barrier to T-cell infiltration and activation in pediatric tumors and provide a strong rationale for combining CAR T-cell therapy with targeted Gal3 inhibition. This engineered CAR T-cell platform represents a promising strategy to enhance therapeutic efficacy in pediatric solid tumors.