Grounded on the bioinformatics insights, this study explores the role of flotillin 1 (FLOT1) in modulating macrophage phenotype and immune evasion in lung cancer cells. The bioinformatics analyses revealed positive correlations between FLOT1 expression and infiltration of M2 macrophages, neutrophils, dendritic cells, and CD4 memory T cells. Furthermore, elevated FLOT1 expression was associated with a poor prognosis in lung cancer patients. Analysis of tumor and adjacent non-tumor tissues from 53 lung cancer patients revealed significantly higher immunohistochemical staining of FLOT1 in tumor tissues, showing positive correlation with the staining intensity of PD-L1. Additionally, staining intensities for markers of M2 macrophages (Arg1), CD4 memory T cells (CD4), dendritic cells (CD83), and neutrophils (CD177) were significantly higher in tumor tissues with high FLOT1 levels. Silencing of FLOT1 was induced in two lung cancer cell lines. Co-culturing in conditioned media of the FLOT1-silenced cancer cells led to reduced chemotactic migration and M2 skewing of macrophages in vitro. Using xenograft models, we observed that FLOT1 silencing weakened tumorigenic activity of A549 cells in mice and reduced M2 macrophage infiltration in tumors. SWI/SNF related BAF chromatin remodeling complex subunit C1 (SMARCC1) was identified as a transcription factor that activated FLOT1 transcription by binding to its promoter. Knockdown of SMARCC1 in lung cancer cells similarly reduced the migration and M2 polarization of macrophages as well as weakened tumorigenesis in mice. However, these effects were counteracted by FLOT1 overexpression. Further analysis of the downstream effectors of the SMARCC1/FLOT1 cascade revealed the enrichment of these factors in ferroptosis-related pathways. Mechanistically, SMARCC1 knockdown led to a decreased GSH:GSSG ratio and increased lipid peroxidation in macrophages, while FLOT1 overexpression restored these changes. Transmission electron microscopic observation revealed typical features of ferroptosis-resistant mitochondria following SMARCC1 knockdown, including fragmented or reduced cristae and increased outer membrane integrity. These mitochondrial changes were mitigated by FLOT1 overexpression. In conclusion, SMARCC1 promotes immune evasion in lung cancer by activating FLOT1 transcription. This activation enhances recruitment and M2 polarization of macrophages, and increases PD-L1 expression, reduces ferroptosis. These findings provide valuable insights into the molecular mechanisms of immune evasion and suggest potential therapeutic targets for lung cancer treatment. KEY MESSAGES: • FLOT1 is associated with poor prognosis in lung cancer patients. • Association between FLOT1 and immune cell infiltration in lung cancer. • Silencing FLOT1 inhibits the recruitment of macrophages by lung cancer cells. • SMARCC1 is highly expressed in lung cancer and promotes the transcription of FLOT1. • FLOT1 overexpression rescues the inhibitory effect of SMARCC1 knockdown on M2 macrophage infiltration and activation of Ferroptosis.