What question did this study set out to answer?

This research aims to identify novel therapeutic targets in rhabdoid tumors using expression profiling of surface proteins.

June 5, 2026

Spatial dissection of ADC/RPT targets defines heterogeneous expression landscapes and therapeutic implications in rhabdoid tumors

Key Points

This research aims to identify novel therapeutic targets in rhabdoid tumors using expression profiling of surface proteins.
Investigated expression of actionable surface proteins for ADCs and RPT in a cohort of 60 rhabdoid tumors.
Prioritized FAP, CXCR4, and IL13RA2 based on transcriptomic analyses and validated with immunohistochemistry.
Integrated spatial and single-nucleus transcriptomic profiling to identify subgroup-specific expression patterns.
51 out of 60 tumors showed positive FAP expression in the stroma with an H-score ≥ 10.
34 out of 60 tumors were positive for CXCR4, indicating potential for targeted therapies.
Identified distinct IL13RA2-positive cell population with melanosomal and stem-like features.

Abstract

BACKGROUND: Rhabdoid tumors (RT) are among the most aggressive pediatric malignancies, characterized by early onset in life, loss of SWI/SNF complex members (SMARCB1 or SMARCA4), and dismal outcomes despite multimodal therapy. Refractory and relapsing RT remain almost uniformly fatal, and targeted or immune-based approaches have yet to demonstrate clinical benefit. METHODS: To explore novel therapeutic vulnerabilities, we systematically investigated the expression of clinically actionable surface proteins that could serve as targets for antibody-drug conjugates (ADCs), radiopharmaceutical therapy (RPT), or cellular immunotherapies. Based on large-scale transcriptomic analyses, we prioritized FAP (fibroblast activation protein), CXCR4 (chemokine receptor 4), and IL13RA2 (interleukin receptor 13 RA2) and performed comprehensive protein-level validation by immunohistochemistry in an unprecedented cohort of 60 rhabdoid tumors spanning all molecular subgroups (ATRT-TYR, ATRT-SHH, ATRT-MYC and eMRT). RESULTS: Integrating these data with spatial and single-nucleus transcriptomic profiling, we identified subgroup- and cell-type-specific expression patterns, including heterogeneous FAP distribution between stromal and tumor compartments and a distinct IL13RA2-positive rhabdoid cell population with melanosomal and stem-like features: Overall 51/60 tumors demonstrated positivity, defined as immunohistochemical H-score above or at least equal to 10, for FAP in the stroma and 34/60 tumors for CXCR4, indicating that a substantial fraction of rhabdoid tumors may be amenable to targeted therapies directed against these epitopes. CONCLUSION: These findings define a set of biologically and clinically relevant surface targets in RT and provide a translational blueprint for rational ADC and RPT target development in pediatric cancer.

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