S100A8-associated inflammatory microenvironment is related to its cell-of-origin and potentiates BRAF inhibitor resistance in papillary craniopharyngioma.

[UNLABELLED] Papillary craniopharyngioma (PCP) is a BRAF mutant inflammation-related tumor that exhibits resistance to targeted therapies. This study aimed to discover mechanisms critical for PCP therapy resistance and identify new therapy target for PCP cells resistant to BRAF V600E inhibition. The microenvironment of PCP was examined using various molecular techniques, including whole-exon sequencing, transcriptome analysis, methylation profiling, and spatial data analysis. Molecular biomarkers, immunohistochemistry (IHC), and multiplex immunofluorescence (mIF) were utilized to explore the relationship between the highly inflammatory microenvironment and tumor origin-related tissue properties (TORTP). Our findings revealed that drug-resistant PCP exhibited high expression of S100A8, a biomarker associated with immune cell activation and inflammation. Crucially, this S100A8-high inflammatory signature was not exclusive to BRAF-mutant PCP. Compared to pituitary tissue, PCP displayed elevated levels of inflammatory markers, particularly S100A8. Spatial analysis within PCPs demonstrated a higher proportion of CK+/S100A8+ cells in the basal layer and S100A8+ cells in the stroma compared to RCC (Rathke’s cleft cyst). The highly S100A8-associated inflammatory microenvironment in PCP was closely linked to leukemia inhibitory factor (LIF). These factors potentiate resistance to BRAF inhibition in papillary craniopharyngioma. The distinct inflammatory microenvironment characterized by high expression of S100A8 is intrinsically linked to TORTP. Combination treatments targeting both the mutated aspects and TORTP-related factors hold significant potential to improve treatment outcomes.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1007/s10238-026-02095-6.