B7-H3 in the tumor microenvironment: Implications for CAR T cell therapy in pediatric solid tumors

B7 homolog 3 (B7-H3, CD276) has emerged as a promising target for chimeric antigen receptor (CAR) T cell therapy, with limited expression in normal tissues and high level cell-surface expression across various tumor types. Clinical studies are ongoing, with a focus on pediatric cancers. As an immune checkpoint molecule of the B7-CD28 family, B7-H3 has a proposed immune-modulatory role, though the precise nature of B7-H3-mediated cell interactions and functional contributions to immune responses are contradictory and likely context-dependent. Within tumors, B7-H3 is expressed also on non-tumor cell types in the tumor microenvironment (TME), including myeloid immune cells, endothelial cells of abnormal vasculature and cancer-associated fibroblasts. Consequently, CAR T cells directed against B7-H3 will not only target tumor cells but also components of the TME, which will affect the nature and outcome of B7-H3-targeted therapeutic immune responses. Here we review the expression of B7-H3 protein in pediatric solid tumors and in various cell types known to infiltrate the TME of solid tumors. On this background, we discuss the potential of B7-H3-targeted CAR T cells to reshape the TME and the key challenges and future directions to improve B7-H3-targeted CAR T cell therapy for pediatric patients with solid cancers.