Highly invasive and quickly fatal, small-cell cancer of the lung (SCLC) continues to be an impossible gulf since discovery. Innate immunity plays an important role in anti-tumor response, among which macrophages lead for an indispensable character. Here, we discovered that macrophage infiltration in SCLC reduced considerably inside a stage-dependent manner, related to the decreased expression of CCL2, a powerful chemoattractant for monocytes. Validated by Nick-qPCR and MassArray methylation analysis, CCL2 expression was inhibited by EZH2-mediated H3K27me3 within the enhancer regions and DNMT1-mediated DNA methylation within the promoter regions, the entire process of that could be turned around by small-molecular compounds, EPZ011989 and Decitabine. Direct cell-cell contact between SCLC cells and macrophages skewed the phenotype of macrophages to become more M1-like. In addition, within an ectopic engraft type of SCLC, disruption of EZH2/DNMT1 function while using combination management of EPZ011989 and Decitabine potently abrogated the inhibition of macrophage infiltration and therefore covered up tumor growth, the result which was impaired by CCL2 neutralization or macrophage depletion. Overall, the work provides new insights in to the role of macrophages in SCLC and establishes a rationale for constructing novel therapeutic avenues for SCLC patients.