Spatial organization of intratumoral microbiome and regional tumor immunity.

Abstract

Solid tumors are spatially heterogeneous ecosystems in which immune recruitment, anatomical access, functional competence, stromal organization, vascularization and physicochemical conditions vary across regions. The conventional "hot-cold" dichotomy therefore obscures the coexistence of immune-inflamed, immune-excluded, immune-suppressed and immune-desert territories within the same lesion. Intratumoral microorganisms add a second layer of heterogeneity, yet microbial signals are often interpreted from bulk abundance without resolving their location, host-cell compartment, viability or functional state. The distinct contribution of this review is the integration of spatial microbial signals with regional immune ecotypes defined independently from microbial presence. Immune-inflamed, immune-excluded, immune-desert, and immune-suppressed regions are assigned from host features of immune recruitment, access to malignant cells, functional competence, and multicellular organization before microbial localization, cellular compartmentalization, and biological state are considered. We examine how intracellular microbial material in malignant cells, phagocyte-associated signals, extracellular biofilms and bacteria-positive microniches may differentially engage HLA-mediated antigen presentation, cGAS-STING or direct STING signaling, TLR-MyD88-TRAF6 pathways, dendritic-cell and natural-killer-cell circuits, and myeloid, stromal and metabolic programs. Depending on microbial identity, burden, persistence and cellular address, these interactions may support cytotoxic immunity or promote chronic inflammation, suppressive myeloid accumulation, neutrophil extracellular traps, regulatory T-cell expansion, T-cell dysfunction and matrix-associated exclusion. We further assess physicochemical selection, microbial metabolism, metastatic persistence, treatment-associated remodeling and spatial multi-omic strategies for defining clinically relevant immunomicrobial niches. Current evidence remains limited by low biomass, contamination risk, incomplete source attribution, cross-sectional sampling and scarce causal validation. Future studies should combine multiregional and longitudinal sampling with orthogonal microbial detection, cell-resolved host profiling, viability and activity measurements, and controlled perturbation. This model reframes tumors as mosaics of regional immune ecotypes in which spatially localized microbial signals acquire context-dependent biological meaning.