A druggable chromatin vulnerability in suppressive neutrophils restores antitumor immunity
- 1University of Michigan
Abstract
Many cancers evade immunity by converting neutrophils into polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), but the chromatin mechanisms that maintain this pathological state remain unclear. Here we show that tumor-induced suppressive neutrophils depend on mSWI/SNF chromatin remodeling. Two orally bioavailable mSWI/SNF ATPase antagonists, a degrader and a catalytic inhibitor, produced immune-dependent tumor control across syngeneic models, including tumors resistant to PD-1 blockade, and enhanced checkpoint therapy without overt toxicity. Treatment rapidly depleted intratumoral PMN-MDSCs, restored functional CD8+ T cells, and blocked tumor explant-induced expansion and suppressive activity of mouse and human PMN-MDSCs. mSWI/SNF antagonism collapsed chromatin accessibility and PU.1/C/EBP{beta} occupancy at regulatory elements that sustain PMN-MDSC identity. Thus, suppressive neutrophils harbor a druggable chromatin vulnerability that can be exploited to restore cancer immunity.
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BibTeX
@misc{yang2026druggable,
title = {{A druggable chromatin vulnerability in suppressive neutrophils restores antitumor immunity}},
author = {F. Yang and Y. Bao and Y. Qiao and G. Cruz and E. Young and R. Mannan and Y. Zhang and M. Goodrich and Y. Cao and J. Luo and R. Paturu and S. Mahapatra and J. C.-Y. Tien and R. Xu and M. Kobayashi and Y. Liu and A. Coleski and F. Su and X. Cao and S. J. Miner and L. Vatan and R. Sudharshan and A. Rao and S. Samajdar and C. Abbineni and M. Ramachandra and J. C. Piel and M. Hentemann and I. Kryczek and W. Zou and L. Xiao and A. M. Chinnaiyan},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.26.754703},
url = {https://www.biorxiv.org/content/10.64898/2026.09.26.754703v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - A druggable chromatin vulnerability in suppressive neutrophils restores antitumor immunity
AU - F. Yang
AU - Y. Bao
AU - Y. Qiao
AU - G. Cruz
AU - E. Young
AU - R. Mannan
AU - Y. Zhang
AU - M. Goodrich
AU - Y. Cao
AU - J. Luo
AU - R. Paturu
AU - S. Mahapatra
AU - J. C.-Y. Tien
AU - R. Xu
AU - M. Kobayashi
AU - Y. Liu
AU - A. Coleski
AU - F. Su
AU - X. Cao
AU - S. J. Miner
AU - L. Vatan
AU - R. Sudharshan
AU - A. Rao
AU - S. Samajdar
AU - C. Abbineni
AU - M. Ramachandra
AU - J. C. Piel
AU - M. Hentemann
AU - I. Kryczek
AU - W. Zou
AU - L. Xiao
AU - A. M. Chinnaiyan
PY - 2026
DA - 2026/09/26
PB - bioRxiv
DO - 10.64898/2026.09.26.754703
UR - https://www.biorxiv.org/content/10.64898/2026.09.26.754703v1
AB - Many cancers evade immunity by converting neutrophils into polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), but the chromatin mechanisms that maintain this pathological state remain unclear. Here we show that tumor-induced suppressive neutrophils depend on mSWI/SNF chromatin remodeling. Two orally bioavailable mSWI/SNF ATPase antagonists, a degrader and a catalytic inhibitor, produced immune-dependent tumor control across syngeneic models, including tumors resistant to PD-1 blockade, and enhanced checkpoint therapy without overt toxicity. Treatment rapidly depleted intratumoral PMN-MDSCs, restored functional CD8+ T cells, and blocked tumor explant-induced expansion and suppressive activity of mouse and human PMN-MDSCs. mSWI/SNF antagonism collapsed chromatin accessibility and PU.1/C/EBP{beta} occupancy at regulatory elements that sustain PMN-MDSC identity. Thus, suppressive neutrophils harbor a druggable chromatin vulnerability that can be exploited to restore cancer immunity.
ER -