Dual tumour-myeloid targeting of glioblastoma with GPNMB CAR-T cells.

Abstract

Glioblastoma is a lethal brain tumour for which current multimodal treatment rarely prevents recurrence¹. Therapeutic failure is driven by extensive intratumoural cellular heterogeneity² with a microenvironment dominated by tumour-associated macrophages that sustain tumour growth and immunosuppression³. Although chimeric antigen receptor (CAR)-T cell therapies are being developed for glioblastoma, sustained response has been undermined by non-uniform antigen expression, antigen loss and microenvironmental barriers that are not directly engaged by tumour-targeting designs⁴. These limitations motivate new strategies that address the disease as a coupled tumour-immune system rather than a single malignant compartment. Here we use a multi-omic target discovery platform to identify GPNMB as a dual-compartment antigen in glioblastoma. Anti-GPNMB CAR-T cells showed potent anti-tumour activity, with long-term disease control in orthotopic patient-derived xenografts and syngeneic glioma models through concomitant depletion of GPNMB⁺ tumour and immunosuppressive myeloid populations. By collapsing tumour control and microenvironmental reprogramming, these findings provide a new strategy for antigen selection and targeting in heterogenous, myeloid-rich solid cancers.