Rhabdoid tumours (RTs) are highly aggressive paediatric malignancies arising as malignant rhabdoid tumours (MRTs) in the kidney or atypical teratoid/rhabdoid tumours (AT/RTs) in the brain. Despite low tumour mutation burden, immune profiling has revealed substantial immune infiltration, including elevated Immune Paediatric Signature Scores (IPASS), robust T-cell and myeloid presence, and SMARCB1-dependent re-expression of endogenous retroviruses, suggesting a reactive tumour immune microenvironment (TIME). Despite these features, RTs remain incurable, highlighting the need to resolve their spatial immune architecture to inform new therapeutic strategies.
We applied a multi-omic approach integrating bulk RNA sequencing, whole-genome sequencing, and spatial transcriptomics and proteomics to characterise the RT TIME. Inflamed tumours (high IPASS) were enriched for chemokine trafficking pathways, whereas immune-cold tumours were dominated by extracellular matrix (ECM) organisation and skeletal muscle–related programs. Spatial transcriptomics revealed a striking absence of inflammatory macrophages within tumour cores, with immune cells sequestered in dense stromal niches. Spatial proteomics further identified “inflamed stromal” regions and a gradient of suppressive myeloid and other immune cell types, consistent with immune exclusion. MRTs displayed dispersed T cells and macrophages across tumour and stromal compartments, whereas AT/RTs were dominated by stromal and perivascular myeloid aggregates. Macrophage transcriptional profiles demonstrated reduced interferon signalling and proliferation in AT/RTs, alongside enhanced tissue remodelling and M2-like polarisation.
These results establish immune exclusion, rather than absence, as a defining feature of RTs, highlighting stromal niches and ECM barriers as key impediments to effective anti-tumour immunity. Notably, tumour-derived leukemia inhibitory factor (LIF), with receptor enrichment on infiltrating myeloid cells, emerges as a candidate signalling axis mediating immune exclusion. Collectively, this study provides the first spatially resolved immune atlas of paediatric RTs, demonstrates how reactive immune cells are confined to stromal regions, and nominates ECM and LIF–LIFR signalling as tractable therapeutic vulnerabilities for these otherwise intractable childhood cancers.