<p>The incidence of colorectal cancer has shown an obvious upward trend worldwide. The prognostic prediction of CRC has not been well established. Based on immunohistochemistry staining, the expression and scoring of TIPE2 and CD8, CD20, and CD66b were evaluated and grouped. The clinicopathological parameters and IHC scores were analyzed and showed by Kaplan-Meier plots. High TIPE2 expression in CRC and normal tissues correlated with a better OS. In contrast, high CD8 and CD20 expression in CRC and normal tissues correlated with a worse OS. High CD66b expression in normal tissues was associated with a worse OS. Lasso and Cox analysis showed that N-stage, CA199, and CD8 in adjacent normal tissues were independent risk factors for OS. Grade and TIPE2 expression in cancer tissues were independent protective factors for OS in CRC patients. Moreover, the nomogram was constructed to predict the 1-, 3- and 5-year overall survival and validated by the calibration curves, receiver operating characteristic curves and decision curve analysis curves. Correlation analysis revealed that TIPE2 and CD8 were positively associated with PD-1 and TIM-3, indicating a potential link between TIPE2 and T cell exhaustion in colorectal cancer. TIPE2 combined with immune markers such as CD8, CD20, and CD66b in the TME can be used as biomarkers of disease progression and prognosis in CRC patients.</p>