S100A4 Is a Targetable Regulator of Immune Suppression in Glioblastoma
- 1Houston Methodist Research Institute
Abstract
Glioblastoma (GBM) is a highly aggressive brain tumor that remains largely refractory to immunotherapy owing to a profoundly immunosuppressive tumor microenvironment (TME). Here, we use mouse models of GBM to identify S100A4 as an actionable regulator of immune suppression and demonstrate that its inhibition converts GBM into an immunotherapy-responsive state. Genetic knockdown of S100a4 in glioma cells reprogrammed the GBM TME, enhancing CD8 T cell infiltration and effector function while promoting maturation of antigen-presenting cells. These changes translated into significant survival benefits across diverse molecular subtypes of GBM. Therapeutically, a novel S100A4/Transferrin Receptor (TfR) bispecific antibody phenocopied S100a4-KD and showed significant therapeutic efficacy, particularly in combination with PD-1 blockade. Notably, BsA+anti-PD1 combination treatment generated tertiary lymphoid-like structures in GBM. Together, these findings establish S100A4 as a targetable driver of immune evasion in GBM and provide a translational strategy for overcoming resistance to immunotherapy in this lethal disease.
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BibTeX
@misc{wong2026s100a4,
title = {{S100A4 Is a Targetable Regulator of Immune Suppression in Glioblastoma}},
author = {T. Wong and J.-S. Leu and M. Faisal and N. H. Abdelfattah and W. Xiong and F. Leonard and Y. Ali and D. Jimenez and H. N. Tran and S. Y. Jung and S. Gulnap and R. Kang and J. Maldonado and Z. An and N. Zhang and K. Yun},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.10.765528},
url = {https://www.biorxiv.org/content/10.64898/2026.11.10.765528v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - S100A4 Is a Targetable Regulator of Immune Suppression in Glioblastoma
AU - T. Wong
AU - J.-S. Leu
AU - M. Faisal
AU - N. H. Abdelfattah
AU - W. Xiong
AU - F. Leonard
AU - Y. Ali
AU - D. Jimenez
AU - H. N. Tran
AU - S. Y. Jung
AU - S. Gulnap
AU - R. Kang
AU - J. Maldonado
AU - Z. An
AU - N. Zhang
AU - K. Yun
PY - 2026
DA - 2026/11/10
PB - bioRxiv
DO - 10.64898/2026.11.10.765528
UR - https://www.biorxiv.org/content/10.64898/2026.11.10.765528v1
AB - Glioblastoma (GBM) is a highly aggressive brain tumor that remains largely refractory to immunotherapy owing to a profoundly immunosuppressive tumor microenvironment (TME). Here, we use mouse models of GBM to identify S100A4 as an actionable regulator of immune suppression and demonstrate that its inhibition converts GBM into an immunotherapy-responsive state. Genetic knockdown of S100a4 in glioma cells reprogrammed the GBM TME, enhancing CD8 T cell infiltration and effector function while promoting maturation of antigen-presenting cells. These changes translated into significant survival benefits across diverse molecular subtypes of GBM. Therapeutically, a novel S100A4/Transferrin Receptor (TfR) bispecific antibody phenocopied S100a4-KD and showed significant therapeutic efficacy, particularly in combination with PD-1 blockade. Notably, BsA+anti-PD1 combination treatment generated tertiary lymphoid-like structures in GBM. Together, these findings establish S100A4 as a targetable driver of immune evasion in GBM and provide a translational strategy for overcoming resistance to immunotherapy in this lethal disease.
ER -