Multi-Niche Microbiome Alterations in Endometrial Cancer: Drivers, Biomarkers and Translational Targets

Endometrial cancer (EC) is the commonest gynecological malignancy in high-income countries and one of the few solid tumors whose incidence and mortality are rising despite advances in oncological care. Conventional hormonal, metabolic and genetic risk factors fail to fully explain EC tumorigenesis, and the multi-niche human microbiome has emerged as a novel, modifiable regulatory axis governing EC onset, progression and immunotherapy responsiveness. However, existing reviews have largely examined individual anatomical sites in isolation, and a cross-compartment synthesis that integrates the gut, cervicovaginal, uterine cavity, and intratumoral niches-together with their mechanistic and therapeutic implications-remains lacking. This narrative review screened English articles from PubMed, Web of Science, Scopus and Google Scholar using keywords covering EC, microbiome, reproductive tract microbiome alterations, the estrobolome and immune checkpoint inhibitors (ICIs), prioritizing prospective cohorts, clinical trials and multi-omics mechanistic studies. We synthesize evidence across four interconnected niches and integrate them into a unified mechanistic framework. Reproducible compartmental signatures characterize EC: cervicovaginal samples show severe Lactobacillus depletion and enrichment of pathogenic anaerobes including Porphyromonas, Prevotella and Atopobium; malignant endometrial tissues display elevated α-diversity dominated by Anaerococcus, Peptoniphilus and Gardnerella, together with poorly explored fungal community shifts; the intratumoral niche harbors distinct taxa that directly modulate tumor proliferation, immune evasion and therapeutic responsiveness; and gut microbiome alterations deplete short-chain fatty acid-producing Firmicutes while expanding β-glucuronidase-rich Enterobacteriaceae, driving estrogen reactivation via the estrobolome and systemic pro-tumor inflammation. The PRIMMO trial further validates gut microbial clusters as predictive biomarkers of pembrolizumab efficacy in recurrent EC. By positioning the intratumoral microbiome as a distinct niche and linking multi-niche alterations to hormonal, inflammatory, immunological and genotoxic pathways, this review provides a new cross-compartment perspective that reframes the microbiome as both a mechanistic contributor and a translational target in EC. Standardized analytical workflows and large-scale prospective cohorts are urgently needed to translate these discoveries into routine clinical practice.