Tumor cell–derived IFN spatially reprograms osteopontin-enriched macrophage niches to promote PARP inhibitor resistance
Dan Liu, Kangjia Tao, Cheng Xu, Wen Yang, Chujun Cai, Cui Feng, Kairong Xiong, Sisi Wu, Yaying Lin, Zikun Peng, Jianhua Chi, Wen Pan, Qing Zhong, Jiahao Liu, Xiong Li, Xingzhe Liu, Dongchen Zhou, Ding Ma, Guang-Nian Zhao, Yu Xia, Yong Fang, Qinglei Gao
Dan Liu, Kangjia Tao, Cheng Xu, Wen Yang, Chujun Cai, Cui Feng, Kairong Xiong, Sisi Wu, Yaying Lin, Zikun Peng, Jianhua Chi, Wen Pan, Qing Zhong, Jiahao Liu, Xiong Li, Xingzhe Liu, Dongchen Zhou, Ding Ma, Guang-Nian Zhao, Yu Xia, Yong Fang, Qinglei Gao
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Research Article Immunology Oncology

Tumor cell–derived IFN spatially reprograms osteopontin-enriched macrophage niches to promote PARP inhibitor resistance

Abstract

Poly (ADP-ribose) polymerase inhibitors (PARPis) benefit homologous recombination-deficient (HRD) malignancies, yet resistance remains a major challenge. Leveraging specimens from a prospective neoadjuvant niraparib monotherapy trial in treatment-naive, high-grade serous ovarian cancer, we integrated PhenoCycler-Fusion spatial profiling, scRNA-Seq, and multiplex immunohistochemistry to identify 2 therapeutic-modulated cellular neighborhoods: an IFN+ tumor cell–enriched niche that expands in resistant lesions and a niche enriched in tumor-associated macrophage (TAM) that persists but acquires enhanced immunosuppressive features. Mechanistically, sustained tumor cell–derived IFN induced osteopontin (SPP1) expression in TAMs via STAT signaling, creating immunosuppressive niches enriched in Tregs and myofibroblastic cancer–associated fibroblasts with intensified cell-cell interactions. SPP1 directly suppressed T cell signaling and effector function. High baseline SPP1+ cells predicted lower response rate (30.0% vs. 76.2%; P = 0.021) and shorter progression-free survival (median 13.5 vs. 28.3 months; P = 0.0006). In HRD mouse models, SPP1 blockade restored PARPi sensitivity, reversed acquired resistance, and enhanced T cell cytotoxicity—effects abrogated in immunodeficient mice, confirming immune dependence. These data establish a spatial IFN-SPP1 axis whereby persistent tumor cell IFN reprograms TAMs to promote PARPi resistance, position SPP1 as a key therapeutic target and prognostic biomarker for this therapy, and underscore therapeutic potential of microenvironment-targeted strategies to overcome PARPi resistance.

Authors

Dan Liu, Kangjia Tao, Cheng Xu, Wen Yang, Chujun Cai, Cui Feng, Kairong Xiong, Sisi Wu, Yaying Lin, Zikun Peng, Jianhua Chi, Wen Pan, Qing Zhong, Jiahao Liu, Xiong Li, Xingzhe Liu, Dongchen Zhou, Ding Ma, Guang-Nian Zhao, Yu Xia, Yong Fang, Qinglei Gao

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Figure 3

IFNG+ tumor cell–enriched CNs and TAM-CNs are associated with niraparib resistance.

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IFNG+ tumor cell–enriched CNs and TAM-CNs are associated with niraparib ...
(A) Forty CNs were computationally identified through k-nearest neighbor graph clustering of 71 annotated cell subtypes. CN annotations reflect dominant cellular compositions. (B) Therapeutic modulation of CN29_TAM and CN12_Epi_IFNG+. Voronoi diagrams illustrating spatial distributions of CN29 and CN12. (C) Box plots quantifying proportions of CN12_Epi_IFNG+ within epithelial (Epi) CNs and CN29_TAM within stroma CNs in pretreatment (Pre) (n = 25), post-niraparib responder (R) (n = 20), and post-niraparib nonresponder (NR) (n = 18) clinical specimens. (D) Heatmaps illustrating the log2-fold changes in abundance of epithelial CNs (left) or stroma CNs (right) across 3 comparisons (R versus Pre; NR versus Pre; NR versus R). (E and F) Donut plots displaying cellular composition within CN12_Epi_IFNG+ (E) and CN29_TAM (F). (G) Violin plots comparing the normalized protein expression profiles of TAMs and T cells within CN29 versus other CNs. (H) Multiplex immunofluorescence co-localization analyses. Upper panel: Spatial interactions of CD68+ cells (TAMs, orange) with adjacent EPCAM+, PD-1+, or FOXP3+ cells. Lower panel: CD3E+ (T cells, green) with adjacent EPCAM+, PD-L1+, or CD68+ cells. The violin plots compare normalized protein signals detected on TAMs (upper) and T cells (lower) within CN29 versus other CNs. Statistical significance was determined by 2-tailed Wilcoxon rank-sum test with Benjamini-Hochberg correction (C and D); Padj values are reported. *Padj < 0.05, **Padj < 0.01, ***Padj < 0.001.