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Single\u2010cell RNA sequencing has greatly improved our understanding of these tumors, but the method lacks cellular tissue context and spatial information about local signaling dynamics. To address this, we profiled untreated and chemotherapy\u2010treated high\u2010risk neuroblastomas from archived, formalin\u2010fixed, paraffin\u2010embedded (FFPE) tissues from two patients using spatial transcriptomics. We confirmed the transcriptional and cellular heterogeneous nature of the neuroblastoma microenvironment and identified several unique spatial niches and patterns. In one of the treated tumors, a spatially constrained cluster of undifferentiated and 11p\u2010gained cancer cells was identified, surrounded by a rim of macrophages. A signaling interaction between the chemokine <jats:italic>CCL18<\/jats:italic> and its receptor <jats:italic>PITPNM3<\/jats:italic> was predicted between these cells. In the other tumor, we identified a stromal cluster with high transcriptional similarity to the adrenal cortex. These adrenocortical\u2010like cells expressed several oncogenic ligand\u2010encoding genes (e.g. <jats:italic>ALKAL2<\/jats:italic> and <jats:italic>NRTN<\/jats:italic>), which were predicted to communicate with neighboring cancer cells that expressed the corresponding receptors (e.g. <jats:italic>ALK<\/jats:italic>, <jats:italic>RET<\/jats:italic>). Several of these interactions were further validated experimentally and were shown to be clinically relevant. Collectively, our spatial analysis identifies multiple previously unrecognized signaling axes that may offer novel therapeutic options in neuroblastoma. \u00a9 2025 The Author(s). <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6457","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T11:34:36Z","timestamp":1754652876000},"page":"181-195","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Spatial transcriptomics exploration of the primary neuroblastoma microenvironment in archived <scp>FFPE<\/scp> samples unveils novel paracrine interactions"],"prefix":"10.1002","volume":"267","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1286-4485","authenticated-orcid":false,"given":"Joachim 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