Table 2:

Spatially distinct tumor immune microenvironments, as per Hammerl et al.⁷⁷

TIME Category	Spatial features, Meta-signatures, Immune characteristics
Ignored (analogous to immune desert)	Classical immunological “cold” landscape, with sparse CTL infiltration, but may include the presence of CD163+ myeloid cells and M2 macrophages Prominent signatures and gene expression of the WNT and PPARG/RXR pathways. Prominent collagen deposition and production of chemo repellents Not primary anti-PD1 responsive, but TONIC trial data reveals tumor subsets that can be primed with Cisplatin and Doxorubicin Therapeutic focus should be on blockers of the WNT pathway, drugs that target M2 macrophages (e.g., the CSF1R inhibitor, pexidartinib).
Excluded (analysis to stromal restricted)	“Cold” tumor variant with T-cell exclusion, but not distinguishing between margin and stromal spatial distributions Dysplastic stroma, with prominent collagen deposition, Prominent expression of TGF-β and VEGF pathways, which contribute to T-cell evasion. Not primary anti-PD1 responsive, but TONIC trial data reveal tumor subsets can be primed by Cisplatin and Doxorubicin Exhibit a pro-inflammatory phenotype with elevated IL-17 signature; Therapeutic focus on the stromal effects, leading to T cell exclusion, including inhibitors of the TGF-β pathway, inhibitors of VEGF receptor kinases.
Inflamed (analogous to fully inflamed)	Inflamed phenotype, with abundant CD8+ T-cells; widespread distribution, also includes M2 macrophages. High TCR clonality, high DC density, high expression of ICD-associated biomarkers and evidence of CTL cytotoxicity Increased expression of ICI receptors, reflecting a negative feedback loop associated with T-cell immunity (Figure 17B) Phenotype of choice for ICI therapy, including combination of multiple ICIs or the use of CSF1R inhibitors targeting M2 macrophages; Reactivation of type I IFN pathway may help to boost antigen presentation.