مقالات پذیرفته شده در نهمین کنگره بین المللی زیست پزشکی
Targeting PD-1⁺ NK Cells and JAK/STAT-Mediated Chemoresistance in High-Grade Serous Ovarian Carcinoma: Insights from Spatially Resolved Omics
Targeting PD-1⁺ NK Cells and JAK/STAT-Mediated Chemoresistance in High-Grade Serous Ovarian Carcinoma: Insights from Spatially Resolved Omics
kimia Asi Ebrahimi,1,*Mahdi Arfaee,2Sahar rasouli,3
1. Department of Biology, Islamic Azad University., Zanjan Branch, Zanjan, Iran1 2. Department of molecular medicine university of Pavia Pavia Italy 3. Department of Hematology, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
Introduction: High-grade serous ovarian carcinoma (HGSC) is one of the most aggressive gynecological malignancies, characterized by late clinical presentation, rapid progression, and frequent relapse following platinum-based chemotherapy. Resistance to standard treatment remains the primary challenge limiting long-term survival. Recent progress in immuno-oncology, molecular signaling research, and spatially resolved omics has provided valuable insights into the biological mechanisms underlying tumor progression and therapy resistance. These advances have opened avenues for developing combinatorial and precision-based therapeutic approaches.
Methods: We applied an integrated experimental framework to investigate the drivers of HGSC progression and chemoresistance. Immune profiling was conducted to characterize tumor-infiltrating immune cell subsets and their functional states. Molecular pathway analyses were performed to assess oncogenic signaling, with a particular focus on JAK/STAT activation. In parallel, spatial proteomics and transcriptomics were employed to capture tissue-level heterogeneity, cell–cell communication, and stromal–epithelial interactions within HGSC tumors across disease stages.
Results: Our analyses revealed a distinct subset of PD-1⁺ natural killer (NK) cells within the tumor microenvironment that displayed impaired cytotoxic activity. Functional restoration of these cells through combined immune checkpoint blockade suggests a therapeutic opportunity for NK cell–directed immunotherapies. Moreover, aberrant activation of the JAK/STAT pathway, driven by JAK1 upregulation, was identified as a central mechanism of platinum resistance. Pharmacological inhibition of this pathway significantly re-sensitized tumor cells to chemotherapy, highlighting its potential as a targetable vulnerability. Spatially resolved proteomic and transcriptomic analyses further uncovered early-stage alterations in cell-type–specific expression, metabolic heterogeneity, and stromal–epithelial signaling, collectively providing mechanistic insights into tumor initiation and progression.
Conclusion: These findings underscore the interplay of immune dysfunction, oncogenic signaling, and spatial heterogeneity in HGSC biology. Therapeutic strategies that restore PD-1⁺ NK cell activity, inhibit JAK/STAT signaling, and incorporate spatial omics–derived biomarkers hold promise for advancing precision oncology in ovarian cancer. Such integrative approaches may overcome platinum resistance, enhance treatment efficacy, and enable earlier detection and prognostication, ultimately improving patient outcomes.