A druggable chromatin vulnerability in suppressive neutrophils restores antitumor immunity

Yang, F.; Bao, Y.; Qiao, Y.; Cruz, G.; Young, E.; Mannan, R.; Zhang, Y.; Goodrich, M.; Cao, Y.; Luo, J.; Paturu, R.; Mahapatra, S.; Tien, J. C.-Y.; Xu, R.; Kobayashi, M.; Liu, Y.; Coleski, A.; Su, F.; Cao, X.; Miner, S. J.; Vatan, L.; Sudharshan, R.; Rao, A.; Samajdar, S.; Abbineni, C.; Ramachandra, M.; Piel, J. C.; Hentemann, M.; Kryczek, I.; Zou, W.; Xiao, L.; Chinnaiyan, A. M.

doi:10.64898/2026.09.26.754703

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bioRxiv · 10.64898/2026.09.26.754703

A druggable chromatin vulnerability in suppressive neutrophils restores antitumor immunity

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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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Yang, F., Bao, Y., Qiao, Y., Cruz, G., Young, E., Mannan, R., Zhang, Y., Goodrich, M., Cao, Y., Luo, J., Paturu, R., Mahapatra, S., Tien, J. C.-Y., Xu, R., Kobayashi, M., Liu, Y., Coleski, A., Su, F., Cao, X., Miner, S. J., Vatan, L., Sudharshan, R., Rao, A., Samajdar, S., Abbineni, C., Ramachandra, M., Piel, J. C., Hentemann, M., Kryczek, I., Zou, W., Xiao, L., Chinnaiyan, A. M.. 2026-09-28. A druggable chromatin vulnerability in suppressive neutrophils restores antitumor immunity. https://doi.org/10.64898/2026.09.26.754703

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