Post-Receptor Dissociation of Estrogen Signaling in Macrophage-Infiltrated Meningiomas: A Multi-Method Deconvolution Study of 968 Transcriptomes

Background. Meningiomas exhibit well-established hormonal biology, yet no study has examined whether myeloid immune infiltration interacts with estrogen-responsive transcription in this tumor type. Methods. We applied three-method consensus immune deconvolution (EPIC, MCPcounter, CIBERSORTx) to 968 harmonized meningioma RNA-seq transcriptomes from five public datasets, stratified by Thirimanne et al. (2024) transcriptomic subtypes. Competitive gene set enrichment compared macrophage-high versus macrophage-low tertiles with sex-adjusted, purity-adjusted, and method-independent sensitivity analyses. Survival modeling tested both total macrophage burden and a decomposed microglia-to-macrophage ratio validated against single-cell ground truth (pseudo-bulk r = 0.77). Results. Macrophage-high tumors showed significant suppression of estrogen response gene sets (FDR = 4.9 x 10-5) despite paradoxical ESR1 upregulation (log2FC = +0.40, FDR = 2.5 x 10-26) and PGR downregulation (log2FC = -0.34, FDR = 2.7 x 10-3), indicating post-receptor transcriptional disruption. This signal strengthened after sex adjustment (FDR = 1.9 x 10-6) and was confirmed across a multi-layer sensitivity battery (eleven analyses including reference-matrix-independent, purity-adjusted, rotation-based self-contained, and empirical-null tests; all FDR < 3 x 10-4 in the relevant convergent tests). Myeloid infiltration was strongly subtype-dependent (Kruskal-Wallis p = 7.4 x 10-16) but grade-independent (p = 0.399), with CSF1R enriched in the macrophage-dominant Cluster B. Neither total macrophage score (HR = 0.90, p = 0.53; N = 102) nor a decomposed microglia/macrophage ratio (HR = 0.92, p = 0.46; N = 101) predicted recurrence-free survival. Conclusions. The pre-registered primary endpoint - macrophage infiltration score predicting recurrence-free survival - was not supported; the estrogen-immune dissociation emerged from secondary exploratory gene-set analysis and requires independent validation. Macrophage-infiltrated meningiomas exhibit a previously unreported dissociation between maintained ESR1 expression and suppressed estrogen-responsive transcription, with implications for hormonal therapy stratification.