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 1

TAMs persist in niraparib nonresponse tumors.

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TAMs persist in niraparib nonresponse tumors. (A) Experimental workflow ...
(A) Experimental workflow for longitudinal tumor sampling and multimodel profiling in the NANT trial. (B) Antibody panel design for 39-protein spatial phenotyping, with background colors marking epithelial (blue) or TME (green) cells, or both (orange). (C) Uniform manifold approximation and projection (UMAP) of single cells color-coded by major lineage (lower), with bar plots quantifying relative cellular abundances (upper). (D) Heatmap of z score–normalized protein levels for canonical lineage markers across cell clusters. (E) PCF images (left: multiplex marker overlay; right: Voronoi tessellation) from a representative region (TMA4_K_3). (F) UMAP of single cells color coded by TAM and DC lineages, with plots showing the normalized protein levels of CD11c. (G) Comparative analysis of cell-type proportions across treatment phases and response categories. Pretreatment (n = 25), post-niraparib responders (R) (n = 21), and nonresponders (NR) (n = 18) were analyzed. Box plots show medians with IQRs. Statistical significance was determined by 2-tailed Wilcoxon rank-sum test with Benjamini-Hochberg correction. *Padj < 0.05, **Padj < 0.01, ***Padj < 0.001.