Decoding meningioma prognosis with multi-omics: macrophage diversity, immune-CNV interplay, and novel SPP1-targeted...

Meningiomas exhibit significant tumor heterogeneity leading to diverse prognosis of patients. While DNA methylation (DNAme)-based classification has shown good performance in subtyping of meningiomas, single-cell transcriptomics offer an opportunity to further explore cell population activity. Understanding the functional states of macrophage populations is especially critical in meningiomas, given their established roles in tumor progression and therapeutic response.

We performed integrated multi-omics clustering of DNAme and bulk RNA-seq data from 302 paired meningioma samples. This identified molecular types characterized by distinct survival, copy number variation (CNV), immune infiltration, and pathway enrichment profiles. Single-cell RNA-seq (scRNA-seq) validated CNV findings and enabled deconvolution of type-specific macrophage populations using SCISSOR, while scRank assessed candidate genes to identify therapeutic targets.

We identified five meningioma molecular types (CS1-CS5) with distinct recurrence risks, survival, CNV landscapes, and immune microenvironments: Proliferative (CS1), Metabolic (CS2), Mixed (CS3), Immune-Enriched (CS4), and NF2-Wild-Type (CS5). CS4 was featured by high macrophage infiltration, while CS5 showed immune-desert characteristics. Type-specific CNV profiles showed chromosome 22 deletions relating to immune infiltration, and SPP1-centered gene networks highlighted its regulatory role in macrophage plasticity. Particularly, SPP1 upregulation associated with poor prognosis in CS1 and downregulation likely contributed to better outcomes in CS4. Drug sensitivity analyses identified the potential of targeting SPP1 for macrophage reprogramming in future type-directed therapies.

Our meningioma prognostic stratification characterized macrophage functional heterogeneity and CNV-driven immune microenvironment disparities. We found SPP1 as a critical regulator for macrophage function and offering a promising candidate for future treatment to target in an aggressive molecular type.