CD13 identifies S100A4⁺ immunosuppressive monocytes and predicts temozolomide benefit in glioblastoma

Glioblastoma (GBM) is an immunologically "cold" tumor in which S100A4-driven immunosuppressive myeloid cells promote progression and resistance. However, the specific immune subpopulation that intrinsically expresses S100A4 and the corresponding cell surface targets remain poorly defined.

S100A4 expression was profiled across immune subsets in healthy human bone marrow and peripheral blood by flow cytometry. TCGA GBM datasets were used to identify S100A4-correlated surface markers, and CD13 (encoded by ANPEP) was validated across the Human Protein Atlas, Immgen, GEO and single-cell RNA-seq datasets. The functional link between CD13, S100A4, and TGFβ was assessed by network analysis and correlation. Drug response analysis was conducted using GEPIA 3 platform.

Monocytes were the predominant S100A4-expressing population in both bone marrow and peripheral blood. CD13 emerged as the surface marker most significantly correlated with S100A4 in GBM. CD13⁺ monocytes co-expressed high levels of S100A4 and were transcriptionally positioned between monocytic and granulocytic lineages. These cells displayed a strong association with TGFβ signaling, suggesting a CD13-TGFβ-S100A4 immunosuppressive axis. Notably, temozolomide conferred a significant survival benefit specifically in CD13-high GBM patients.

CD13 marks S100A4-high immunosuppressive monocytes in GBM and represents an accessible surface target for monitoring and potentially depleting this pathogenic population. The CD13-S100A4-TGFβ axis and the predictive value of CD13 for temozolomide response offer a translational framework for advancing GBM immunotherapy.