IL-17D reprograms CD93+ antigen-presenting cells in the glioblastoma microenvironment

The immunosuppressive microenvironment is a hallmark of Glioblastoma (GBM), limiting the efficacy of contemporary immunotherapies. While the central nervous system (CNS) relies on specialized cytokine networks to maintain immune homeostasis under physiological conditions, how these homeostatic signals are subverted during gliomagenesis remains poorly understood. Here, we report that interleukin-17D (IL-17D) is a CNS-intrinsic tumor suppressor whose expression is downregulated during gliomagenesis. Restoring IL-17D substantially extends survival in orthotopic GBM models by selectively reprogramming the myeloid compartment. Mechanistically, IL-17D engages its receptor CD93 to assemble a novel costimulatory receptor complex with SCARB1 in a lipid raft-dependent manner. This structural assembly engages FYN/BCAP to trigger PI3K/Akt/NF-κB signaling, effectively inverting the function of SCARB1 from tolerogenic efferocytosis to active antigen presentation. Our study demonstrated that the restoration of IL-17D expression reshaped the GBM immune landscape, highlighting its potential as a therapeutic target to enhance the efficacy of immunotherapy.