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 4

Enhanced spatial interaction between CNs in niraparib-resistant lesions.

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Enhanced spatial interaction between CNs in niraparib-resistant lesions....
(A) Donut plots illustrating the cellular constituents of CN12_Epi_IFNG+ in pretreatment (left) and post-niraparib nonresponder (NR) (right) specimens. (B) Representative nearest-neighbor distances images of the proximity of CN29_TAM to CN12_Epi_IFNG+ with color-coded phenotypes in pretreatment (left) and post-niraparib NR (right) specimens. (C) Density plots illustrating the distribution of distances from all stromal CN centroids to their nearest-neighbor CN12_Epi_IFNG+ aggregated across all samples. The top 6 nearest stromal CNs are shown, with dotted vertical lines representing the median distance for each respective CN. (D) Density plots comparing the distance from the CN29_TAM to CN12_Epi_IFNG+ across clinical cohorts: pretreatment (blue), responders (R) (light orange), and nonresponders (dark red). Statistical significance was determined by Kolmogorov-Smirnov test. (E) Heatmaps of Pearson correlation coefficients (color of the square) and pairwise cell-cell interactions scores (circle size) among CN29-TAM niche components. Left: Pretreatment samples (n = 25). Right: Post-niraparib samples (n = 39). (F) Scatter plots illustrating the correlation between total TAM frequency (of stroma) and the proportion of CD4+FOXP3+PD1+ T cell subsets following niraparib treatment based on PCF (n = 49; left) and scRNA-Seq (n = 14; right), include both R and NR lesions. (G) Covariation of TAMs and immune cell abundances across pretreatment (n = 25; left) and post-niraparib (n = 49; right) samples, based on PCF data. Pearson correlation analysis. *P < 0.05. (H) Covariation of cell abundances within niraparib posttreatment tumors (n = 14), based on scRNA-Seq. Pearson correlation analysis was used. *P < 0.05.