Multi-omics decodes how microbiota-residing spatial niches mediate cancer progression and therapy response

Abstract

Research on the intratumoral microbiota is shifting from descriptive analyses of presence and abundance toward understanding its spatial heterogeneity and local function. Here we propose the concept of the microbiota-residing spatial niche (MRSN), defined as a functional unit formed by interactions between microbiota and neighboring tumor, immune, and stromal cells within a defined spatial context, and characterized by four key features: spatial discernibility, functional consistency, microbial dependency, and clinical relevance. In this review, we discuss the limitations of single-omics approaches and present a framework centered on spatial multi-omics. This framework integrates spatial transcriptomics, multiplex immunoimaging, spatial metabolomics, and graph neural networks, enabling a stepwise analysis that first localizes microbiota, then characterizes their surrounding cellular neighborhoods, and finally validates their functional roles. We classify MRSNs into immunosuppressive, immunostimulatory, protumorigenic, and antitumorigenic types, and demonstrate how they modulate therapy responses through local metabolic remodeling and immune regulation. We also contrast the systemic immunomodulatory effects of gut microbiota with the localized influence of intratumoral microbiota. Finally, we discuss challenges in technical validation, temporal dynamics, and model translation, and propose strategies for precision interventions targeting niche vulnerabilities and clinical stratification. This framework provides a unified conceptual basis for understanding intratumoral microbiota functions and informs next-generation spatially guided therapeutic strategies.

Keywords

Intratumor microbiota / Spatial multi-omics / Microbiota-residing spatial niche / Tumor microenvironment / Immunosuppressive niche / Metabolic reprogramming / Immunotherapy response / Spatial heterogeneity

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