Background:Immunotherapy has dramatically changed the landscape of treatment for colorectal cancer (CRC), but there is lack of effective predictive biomarker, especially for tumors with mismatch repair (MMR) proficiency. Immune response relies to cell surface receptors and their interactions, such as cell-cell recognition, binding and adhesion. However, the function of immunoglobulin superfamily (IGSF) genes in tumor immune microenvironment remains uncharacterized. Methods: This study quantified the immune using the gene expression matrix obtained from the public database. Also the associations between IGSF6 gene expression and immune cell infiltration were assessed. The expression levels of IGSF6, CD8+ and CD4+ T cells in cancer tissues from CRC patients were evaluated. Results: IGSF6 was more highly expressed in CRC tumor tissues than corresponding adjacent normal tissues. And IGSF6 was significantly correlated with immune cell infiltration in MMR-proficient patients. Remarkably, MMR-proficient patients with high IGSF6 expression showed more sensitive to immunotherapy and chemotherapy than those with low IGSF6 expression. Conclusions: In summary, IGSF6 could be a novel biomarker to evaluate immune infiltration and predict therapeutic effect for MMR-proficient CRC.