Targeting legumain-mediated cell-cell interaction sensitizes glioblastoma to immunotherapy in preclinical models

Tumor-associated macrophages (TAMs) are the most prominent immune cell population in the glioblastoma (GBM) tumor microenvironment and play critical roles in promoting tumor progression and immunosuppression. Here we identified that TAM-derived legumain (LGMN) exhibited a dual role in regulating the biology of TAMs and GBM cells. LGMN promoted macrophage infiltration in a cell-autonomous manner by activating the GSK3β/STAT3 pathway. Moreover, TAM-derived LGMN activated integrin αv/AKT/p65 signaling to drive GBM cell proliferation and survival. Targeting of LGMN-directed macrophage (inhibiting GSK3β and STAT3) and GBM cell (inhibiting integrin αv) mechanisms resulted in an antitumor effect in immunocompetent GBM mouse models that was further enhanced by combination with anti-PD-1 therapy. Our study reveals a paracrine and autocrine mechanism of TAM-derived LGMN that promotes GBM progression and immunosuppression, providing effective therapeutic targets to improve immunotherapy in GBM.