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

Lizhi Pang; Songlin Guo; Yuyun Huang; Fatima Khan; Yang Liu; Fei Zhou; Justin D. Lathia; Peiwen Chen

doi:10.1172/JCI186034

Published March 25, 2025 - More info

View PDF

Abstract

Tumor-associated macrophages (TAMs) are the most prominent immune cell population in the glioblastoma (GBM) tumor microenvironment (TME) 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 GSK3b-STAT3 pathway. Moreover, TAM-derived LGMN activated the integrin aV-AKT-P65 signaling to drive GBM cell proliferation and survival. Targeting LGMN-directed macrophage (inhibiting GSK3b and STAT3) and GBM cell (inhibiting integrin aV) mechanisms resulted in an anti-tumor effect in immunocompetent GBM mouse models that was further enhanced when combined with anti-PD1 therapy. Our study reveals a paracrine and autocrine mechanism of TAM-derived LGMN in promoting GBM progression and immunosuppression, providing effective therapeutic targets for improving immunotherapy in GBM.

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

Lizhi Pang,¹ Songlin Guo,² Yuyun Huang,¹ Fatima Khan,¹ Yang Liu,¹ Fei Zhou,¹ Justin D. Lathia,³ and Peiwen Chen¹

Article tools

Metrics

Go to

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

Lizhi Pang,1 Songlin Guo,2 Yuyun Huang,1 Fatima Khan,1 Yang Liu,1 Fei Zhou,1 Justin D. Lathia,3 and Peiwen Chen1

Article tools

Metrics

Go to

Sign up for email alerts

Lizhi Pang,¹ Songlin Guo,² Yuyun Huang,¹ Fatima Khan,¹ Yang Liu,¹ Fei Zhou,¹ Justin D. Lathia,³ and Peiwen Chen¹