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The role of metabolic reprogramming of the tumor immune microenvironment in cancer development and immune escape has increasingly attracted attention. However, the predictive value of differences in metabolism-immune microenvironment on the prognosis of colon cancer (CC) and the response to immunotherapy have not been elucidated. The aim of this study was to investigate changes in metabolism and immune profile of CC and to identify a reliable signature for predicting prognosis and therapeutic response. The metabolism and immune-related differential genes in CC were screened out by differential gene expression analysis. A metabolism and immune related prognostic signature was established by the least absolute shrinkage and selection operator (LASSO) Cox algorithm. The training cohort with 417 patients from The Cancer Genome Atlas (TCGA) database and the validation cohort of 232 patients from GSE17538 were used to confirm the robustness of the prognostic signature. Immunohistochemical staining scores were used to assess gene expression levels in our clinical samples. Gene ontology (GO) analysis, gene set enrichment analysis (GSEA), single nucleotide variation (SNV) analysis, immune infiltration and immune factors analysis were used to explore the characteristics of patients with different subtypes. Multiple cancer immunotherapy datasets were used to assess the response of patients with different subtypes to immune checkpoint inhibitors. We established the Metabolism and Immune-Related Prognostic Score (MIRPS) based on six genes (CD36, PCOLCE2, SCG2, CALB2, STC2, CLDN23) to predict the prognosis of CC patients. We found a correlation between MIRPS and the malignant phenotype, microsatellite subtype, mutation load, and immune escape in CC. Tumors with high MIRPS presented a higher tumor mutation load and a more prominent immunosuppressive microenvironment. This subset of patients may potentially respond well to immune checkpoint inhibitor therapy. MIRPS may be used as a novel prognostic tool for CC and have potential value for immunotherapy response prediction. [ABSTRACT FROM AUTHOR]