Open Access
REVIEW
Spatial Multi-Omics Dissecting Drug Resistance and Therapeutic Vulnerability in Ovarian Cancer: Insights Primarily from High-Grade Serous Carcinoma
Zhewei Zhang1,2, Jie Wu1,2, Kit Ying Chan1,2, Tat San Lau1,2,*, Chi Chiu Wang1,2,3,*
1 Department of Obstetrics and Gynaecology, the Chinese University of Hong Kong, Shatin, Hong Kong
2 Li Ka Shing Institute of Health Sciences, the Chinese University of Hong Kong, Shatin, Hong Kong
3 School of Biomedical Sciences, the Chinese University of Hong Kong, Shatin, Hong Kong
* Corresponding Author: Tat San Lau. Email: 
; Chi Chiu Wang. Email: 
(This article belongs to the Special Issue: Targeting the Tumor Microenvironment: Emerging Insights into Cancer Progression and Therapeutics)
Oncology Research https://doi.org/10.32604/or.2026.085305
Received 08 May 2026; Accepted 27 July 2026; Published online 10 September 2026
Abstract
Drug resistance in ovarian cancer, particularly platinum and immunotherapy resistance, is not a uniform tumor property but arises from spatially discrete microenvironmental niches. Conventional bulk and single-cell sequencing approaches cannot resolve this spatial organization, obscuring the regional heterogeneity that governs therapeutic vulnerability. Spatial multi-omics technologies, including spatial transcriptomics, multiplexed spatial proteomics, and mass spectrometry imaging-based metabolomics, now enable direct interrogation of these resistance niches within intact tissue architecture. This review aims to synthesize how spatial multi-omics redefines the mechanistic understanding of platinum and immunotherapy resistance in ovarian cancer and to propose a framework of spatially resolved biomarkers for niche-specific patient stratification. In high-grade serous ovarian carcinoma, four principal resistance microdomains have been proposed: the perivascular cancer stem-like cell niche, the hypoxic HIF-1α/NRF2/glutathione-rich niche, the cancer-associated fibroblast barrier niche mediating immune exclusion, and the omental adipocyte niche driving fatty acid oxidation-dependent chemoresistance. Spatial analysis further reveals that tertiary lymphoid structures (TLSs) in ovarian cancer harbor terminally exhausted rather than progenitor T cells, which may help to explain paradoxical immunotherapy failure despite immune infiltration. Integration of spatial transcriptomic, proteomic, and metabolomic data generates candidate biomarker scores, including spatial immune infiltration, cancer-associated fibroblast (CAF) organization, metabolic niche, chemoresistance niche, and spatial heterogeneity scores, that are presented here as hypothesis-generating research tools for niche-specific stratification rather than as clinical decision rules. Prospective validation of these spatial biomarkers in clinical trial cohorts represents the critical next step toward spatially informed precision oncology in ovarian cancer.
Keywords
Spatial multi-omics; drug resistance; tumor microenvironment (TME); ovarian cancer; immunotherapy resistance
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