Crosstalk Between CTSB⁺ Glioblastoma Cells and S100A10⁺ Macrophages: A Self-Reinforcing Circuit Promotes Immune Evasion and Limits Response to Immunotherapy.

Authors

Hao Zhang, Nan Zhang, Xisong Liang, Jie Wen, Ziyu Dai, Wantao Wu, Shuyu Li, Songshan Feng, Zaoqu Liu, Zhiwei Xia, Peng Luo, Quan Cheng

Published in

Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e76905. Aug 29, 2026. Epub Aug 29, 2026.

Abstract

Glioblastoma (GBM) establishes a highly immunosuppressive microenvironment through intricate molecular dialogues with tumor-associated macrophages (TAMs), contributing to immunotherapy resistance.
We integrated advanced biological network analyses with multimodal AI to identify CTSB as a key biomarker. Functional validation included GBM-macrophage co-culture systems, chromatin immunoprecipitation (ChIP), dual-luciferase reporter assays, molecular docking, and co-immunoprecipitation (Co-IP). In vivo experiments employed orthotopic (GL261 and CT-2A) and subcutaneous GBM models with lentivirus-mediated CTSB knockdown and anti-PD-1 therapy. Tumor microenvironment dynamics were assessed via in-house generated single-cell RNA sequencing and multiplex immunofluorescence.
Cathepsin B (CTSB) was identified as a critical driver of aggressive GBM progression and poor outcomes. Mechanistically, macrophage-derived IL-6 activates STAT3 in tumor cells, upregulating CTSB expression. Structural and Co-IP analyses revealed CTSB, secreted by tumor cells, binds the C-terminus of macrophage S100A10, reinforcing IL-6 secretion, forming a feedforward loop between CTSB⁺ GBM cells and S100A10⁺ macrophages. This loop enhances tumor growth, invasion, and immune evasion via PD-L1 upregulation. In vivo, CTSB blockade reduced TAM activation, increased CD8⁺ T cell infiltration, and synergized with anti-PD-1 therapy.
This study unveils a targetable GBM-macrophage signaling axis, proposing CTSB inhibition as a strategy to enhance immunotherapy efficacy in GBM patients.

PMID:
42666105
Bibliographic data and abstract were imported from PubMed on 29 Aug 2026.

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