The human monocytic leukemia cell line, THP-1-differentiated macrophages are a useful tool to investigate the physiological significance of tumor-associated macrophages (TAMs). In the tumor microenvironment (TME), TAMs with the M₂-like phenotype play a critical role in the promotion of cancer progression and metastasis by inhibiting the immune surveillance system. We examined the involvement of Ca²⁺-activated K⁺ channel K_Ca3.1in the expression of pro-tumorigenic cytokines and angiogenic growth factors in THP-1-derived M₂ macrophages. THP-1 cells into M₀ macrophages were induced by a treatment with PMA treatment for 24 hr, and then cells were treated with IL-4 and IL-13 for 72 hr to induce the polarization of M₂ macrophages. The expression levels of IL-8 and IL-10 were significantly decreased by treatment with the selective K_Ca3.1 activator, SKA-121 in THP-1-derived M₂ macrophages. Furthermore, under in vitro experimental conditions that mimic extracellular K⁺ levels in the TME, IL-8 and IL-10 levels were both significantly elevated, and these increases were reversed by treatment with SKA-121. Among several signaling pathways potentially involved in the transcriptional regulation of IL-8 and IL-10, respective treatments with ERK and JNK inhibitors significantly repressed their transcriptions, and treatment with SKA-121 significantly reduced the phosphorylated ERK, JNK, c-Jun, and CREB levels. These results strongly suggest that the K_Ca3.1 activator may suppress IL-10-induced tumor immune surveillance escape and IL-8-induced tumorigenicity and metastasis by inhibiting their production from TAMs through both ERK-CREB and JNK-c-Jun cascades.