Protumor Macrophage Polarization Mediated by BMP2/4-ACVR1 Signaling Orchestrates an Immunosuppressive Microenvironment during Tumor Initiation.

[UNLABELLED] Cancer cells are able to evade immunosurveillance 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 a cTME, we generated single-cell RNA sequencing data during the initiation phases of EGFR-driven lung adenocarcinoma. Macrophages in the tumor microenvironment (TME) underwent a state transition from antitumor macrophages to protumor macrophages, which orchestrated the formation of a cTME. Tumor cell-derived BMP2/4 induced the polarization of protumor macrophages, and inhibiting the BMP2/4-ACVR1 axis with an ACVR1 inhibitor converted the cTME into a "hot" TME, resulting in a potent suppression of tumor growth. Furthermore, patients with EGFR-mutant lung adenocarcinoma exhibited similar cTME characteristics to those observed in mice, and high expression of ACVR1 correlated with worse patient prognosis. Overall, in addition to elucidating the role of protumor macrophages in cTME formation, this study pinpoints targeting ACVR1 as a therapeutic strategy for treating EGFR-mutant lung cancers.

[SIGNIFICANCE] In the early stages of lung cancer development, cancer cells reprogram tumor-associated macrophages via BMP2/4-ACVR1 signaling to stimulate the formation of an immunosuppressive tumor microenvironment, establishing ACVR1 as a potential immunotherapeutic target.