Permeabilisation of tumour margins in brain macrometastases using a type-1 receptor selective tumour necrosis factor mutein

Journal article

Background Brain metastasis remains a major clinical challenge. The blood-brain barrier (BBB), which persists in the margins even in late-stage macrometastases, is a major impediment to effective drug delivery, surgery or radiotherapy. The aim of this study was to determine whether a mutein of human tumour necrosis factor (TNF) that is selective for the TNFR1 receptor could increase permeabilisation in the margins of brain metastases, enabling better delineation and more complete treatment. Methods Intracerebral xenograft mouse models of breast cancer (MDA231Br-GFP), melanoma (H1_DL2) and lung cancer (SEBTA) brain metastasis were used to test the efficacy of the TNF mutein (mutTNF) in permeabilising the margins of well-established macrometastases. Changes in tumour permeabilisation were assessed in vivo by gadolinium-enhanced magnetic resonance imaging (MRI) and ex vivo by IgG immunohistochemistry. Results Tumour margin permeabilisation was increased following mutTNF treatment in all three models. The MDA231Br-GFP model showed a significant increase in the extent of both gadolinium enhancement (P<0.01) and IgG extravasation (P<0.05), whilst significant effects were detected by MRI alone in the SEBTA (P<0.01) and H1_DL2 (P<0.05) models. Although a strong trend towards increased IgG extravasation was found in the SEBTA model (P=0.076). Consistent with these findings, the models showed differing degrees of both infiltration and vascular TNFR1 expression at the margins (MDA231Br-GFP > SEBTA > H1_DL2), suggesting a greater sensitivity to mutTNF with increasing marginal invasiveness. Conclusions This work demonstrates the potential of TNFR1 selective mutTNF as an adjuvant strategy to improve tumour margin delineation and enhance therapeutic access in brain metastases.

Authors: Johanssen, VA; Bristow, C; Campbell, SJ; Anthony, DC; Middleton, MR

• Publication status: Accepted
• Peer review status: Peer reviewed
• Publisher: Oxford University Press
• Journal: Neuro-Oncology Advances
• Acceptance date: 2026-08-31
• DOI: 10.1093/noajnl/vdag239
• EISSN: 2632-2498
• Language: English
• Keywords: brain metastasis; tumour margins; mutein; tumour necrosis factor; permeabilisation