Pro-tumor Macrophage Polarization Mediated by BMP2/4-ACVR1 Signaling Orchestrates an Immunosuppressive Microenvironment During Tumor Initiation

Abstract Cancer cells are able to evade immune surveillance by engendering an immunosuppressive “cold” tumor microenvironment (cTME). A better understanding of the mechanisms underlying the establishment of a cTME in the initial phases of tumor formation could help uncover improved immunotherapeutic strategies. To characterize the temporal dynamics of the formation of cTME, we generated single-cell RNA-sequencing data during the initiation phases of EGFR-driven lung adenocarcinoma (LUAD). Macrophages in the TME underwent a state transition from anti-tumor macrophages to pro-tumor macrophages, which orchestrated the formation of a cTME. Tumor cell-derived BMP2/4 induced the polarization of pro-tumor macrophages, and inhibiting the BMP2/4-ACVR1 axis with ACVR1 inhibitor converted the cTME into a “hot” TME (hTME), resulting in a potent suppression of tumor growth. Furthermore, EGFR-mutant LUAD patients exhibited similar cTME characteristics as observed in mice, and high expression of ACVR1 correlated with worse patient prognosis. Overall, in addition to elucidating the role of pro-tumor macrophages in cTME formation, this study pinpoints targeting ACVR1 as a therapeutic strategy for treating EGFR-mutant lung cancers.