Table 4.

Multi-dimensional 2025 framework mapping spatial, stromal, microbial, and vascular dynamics of the TME to immunotherapy efficacy and resistance

TME Axis	Core Mechanism	Key 2025 Tools / Approaches	Therapeutic or Predictive Impact	Challenges / Future Needs	References
TME Phenotypes (Inflamed/Excluded/Desert)	Spatial–functional gradients of immune infiltration shaped by ECM, vasculature, and cytokine milieu	AI-driven spatial classifiers; multiplex IHC+spatial omics	Stratifies ICI responsiveness; guides phenotype-modulating therapies	Overlapping phenotypes; temporal plasticity under therapy	(163)
CAF–TAM–Treg Crosstalk	Paracrine, metabolic, and mechanical loops enforcing immune exclusion and T-cell exhaustion	Single-cell+spatial transcriptomics; ligand–receptor network inference	Identifies combinatorial targets (e.g., C3aR/C5aR, TGF-β, TNFSF14) for stromal reprogramming	Spatial heterogeneity; off-target immune activation risk	(147)
Microbiome–Immune–Tumor Axis	Microbial metabolites (SCFAs, inosine, bile acids) reshape systemic and local immune tone.	Metagenomics+metabolomics; microbial consortia modeling; precision FMT	Enables microbiome-based sensitization to ICI; predictive of resistance	Inter-patient variability; causal directionality unresolved	(153, 164)
TME Barrier Targeting	Vascular normalization+macrophage reprogramming+matrix remodeling synergize for immune access	Perfusion MRI; macrophage-metabolic imaging; biomaterial gradient scaffolds	Enhances drug delivery and T-cell infiltration; prolongs ICI response	Timing of normalization window; risk of hypoxia rebound	(165)