Spatial multi-omics and synergistic nanodelivery of natural products targeting the hypoxia inducible factor 1 alpha lactate axis to remodel the gynecological tumor microenvironment

The hypoxia-driven HIF-1α/lactate metabolic axis establishes a spatially organized metabolic niche in gynecological malignancies, inducing T-cell exhaustion and protein lactylation that drive profound immunotherapy resistance. Integrating recent advances in spatial multi-omics, this review systematically elucidates the role of metabolomics-validated natural products. These agents, including specific monomers like shikonin and complex botanical formulas, downregulate HIF-1α and actively clear localized extracellular lactate. To overcome the inherent pharmacokinetic limitations and poor bioavailability of these natural agents, tumor microenvironment (TME)-responsive nanodelivery systems facilitate precise drug release directly within the hypoxic tumor core. This targeted metabolic remodeling effectively relieves spatial immune exclusion, converting immunologically “cold” tumors into “hot” phenotypes and significantly sensitizing them to immune checkpoint inhibitors (ICIs). Supported by preclinical models and Real-World Evidence (RWE), we propose a tripartite translational blueprint: integrating spatial diagnostics, biomimetic nanodelivery of natural products, and ICI combinatorial strategies to overcome refractory gynecological cancers.