Galanin impairs tumor immunity in glioblastoma by promoting infiltration and ferroptosis resistance of myeloid-derived suppressor cells.

Glioblastoma (GBM) is a highly aggressive and lethal form of brain tumor that resists immunotherapy. Here we show that neuropeptide galanin (GAL) drives immunosuppression and immunotherapy resistance in GBM. Mechanistically, GBM cell-secreted GAL interacts with its receptor GALR3 on monocytic myeloid-derived suppressor cells (mMDSCs), triggering USP51-mediated deubiquitination of estrogen receptor-α, thereby engaging membrane-bound O-acyltransferase domain-containing 1 signaling. This signaling cascade, in turn, promotes the infiltration of immunosuppressive mMDSCs and confers ferroptosis resistance to them in the tumor microenvironment. Targeting mMDSCs through GALR3 inhibition and ferroptosis induction impairs tumor progression and activates antitumor immunity in GBM mouse models. Remarkably, combining this approach with anti-PD1 therapy achieves durable and complete tumor regression in approximately 60% of tumor-bearing mice. Our study elucidates the molecular mechanism underlying GBM immunosuppression and highlights a promising therapeutic strategy to enhance GBM response to immunotherapy.