BACKGROUND: The progression process of lung cancer can be accelerated by M2 macrophages. However, genes that affect M2 macrophage polarization remain unidentified. METHODS: The Cancer Genome Atlas, Gene Expression Omnibus, and Arrayexpress databases were used to obtain open-access data. The analysis of public data was mostly performed with R studio. The RNA levels of specific genes were detected using quantitative real-time PCR. The proliferation ability of the cells was assessed by CCK8, colony formation, and EdU assays. RESULTS: Based on the multiple datasets, we noticed a poor prognosis in patients with high M2 macrophage infiltration. There were 114 genes differentially expressed between high and low M2 macrophages infiltrated samples, regarded as M2 macrophage-related genes. Subsequently, a prognosis prediction signature consisting of ABHD5, HS3ST2, TM6SF1, CAPZA2, LEPROT, HNMT, and MRO was identified and presented a satisfactory performance. The pathway enrichment results revealed a positive correlation between riskscore and enrichment scores for most immunotherapy-related positive terms. Also, there might be an increase in genomic instability among patients at high risk. Interestingly, low risk patients are most likely to benefit from PD-1 therapy, while high risk patients may benefit from CTLA-4 therapy. Meanwhile, the estimated IC50 of seven drugs differs significantly between two risk groups, including Cisplatin, Docetaxel, Doxorubicin, Gefitinib, Paclitaxel, Sunitinib and Vinorelbine. Moreover, further experiments indicated that HNMT was overexpressed and can enhance the proliferation ability in lung cancer cells. CONCLUSIONS: In summary, our study identified the molecules significantly affecting M2 macrophage infiltration and identified a prognosis signature that robustly indicated patients prognosis. Moreover, we validated the cancer-promoting effect of HNMT using experiments.