Abstract The immunosuppressive tumor microenvironment (TME) in glioblastoma (GBM) is predominantly shaped by tumor-associated macrophages (TAMs), yet the key chemokine axes driving immunosuppression and progression remain poorly defined. In this study, we identified the CCL1-AMFR axis as a critical contributor to GBM progression through dual immune-modulatory and tumor-intrinsic mechanisms. Analysis of human glioma datasets and tissue samples revealed that CCL1 - predominantly derived from TAMs - was significantly overexpressed in GBM and correlated with poor patient survival. Functionally, CCL1 recruited Arg1+ immunosuppressive macrophages in an AMFR-dependent manner. Myeloid-specific knockout of either Ccl1 or Amfr in murine models reduced TAM infiltration and extended survival. Although CCL1 can signal through both CCR8 and its recently identified receptor AMFR, AMFR played the dominant role in mediating CCL1-induced tumor cell proliferation and migration by activating the FAK and PI3K-AKT signaling pathways. Importantly, therapeutic neutralization of CCL1 using a monoclonal antibody significantly prolonged median survival in both immunocompetent GL261 murine GBM and BNI1-3 patient-derived xenograft (PDX) models, accompanied by reduced TAM infiltration and attenuated FAK/PI3K-AKT signaling. Our findings establish TAM-derived CCL1 as a pivotal regulator of GBM pathogenesis and demonstrate that targeting the CCL1–AMFR axis disrupts both tumor-intrinsic growth and immunosuppressive TME dynamics, representing a promising therapeutic strategy for this lethal malignancy.
Shen et al. (Fri,) studied this question.