SPP1+ Neutrophils Mediate Resistance to Immune Checkpoint Blockade in BAP1-Inactivated Tumors

作者：Jiahao Shi, Shiyun Huang, Yixiong Zhou, Guopei Zheng, Zhe Zhang, Xianqun Fan, Jianfeng Shen · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/0008-5472.can-24-4962 · 被引用次数：3 · 研究领域：Cancer Immunotherapy and Biomarkers、Immune cells in cancer、Cancer Research and Treatments

BAP1 inactivation, observed across multiple human cancers, is linked to immune checkpoint blockade (ICB) resistance and adverse clinical outcomes. The mechanisms underlying BAP1-associated ICB sensitivity could provide potential targets to enhance ICB efficacy. In this study, we showed that BAP1 inactivation fosters an immunosuppressive tumor microenvironment, marked by increased infiltration of M2-like macrophages and neutrophils. Single-cell transcriptomic analysis revealed an expansion of SPP1+ neutrophils in ICB-treated, BAP1-inactivated tumors. These SPP1+ neutrophils displayed a protumorigenic phenotype and conferred resistance to anti-PD-1 therapy by engaging with cytotoxic T cells via PD-1/PD-L1 signaling. Notably, depletion of neutrophils, but not macrophages, restored sensitivity to ICB in BAP1-inactivated tumors. Mechanistically, BAP1 loss significantly increased C-C motif chemokine ligand 2 (CCL2) secretion, driving neutrophil SPP1+ polarization, delaying neutrophil apoptosis, and promoting ICB resistance. This resistance could be significantly mitigated by targeting the CCL2-C-C chemokine receptor type 2 (CCR2) axis. These results underscore the role of BAP1 in modulating the immune landscape and suggest that targeting CCL2-CCR2-mediated neutrophil polarization may overcome ICB resistance in BAP1-inactivated tumors. SIGNIFICANCE: BAP1 inactivation induces immunotherapy resistance and engenders an immunosuppressive microenvironment by enhancing CCL2 secretion and ...