To elucidate the relationship between circulating cytokines and the prognosis of microsatellite-stable(MSS) colorectal cancer (CRC) patients, we examined the correlation between circulating cytokine levels and tumor immune infiltration microenvironment in this patient population. By conducting a preliminary analysis of the GEO database, we identified five core genes associated with colorectal cancer and further analyzed their impact on immune infiltration. We measured serum cytokine levels and validated the immune infiltration results through immunohistochemical staining of common inflammatory cell markers, including CD3, CD4, CD8, CD163, and FOXP3. Our findings indicate that serum cytokine levels significantly influence immune infiltration in colorectal cancer, particularly IL6 and IFNγ, which play crucial roles. Specifically, the infiltration of M2-type macrophages and CD8 + T cells is correlated with serum levels of IL6 and IFNγ. MSS CRC patients with elevated IL6 expression exhibit improved prognosis.