BACKGROUND: Colorectal cancer (CRC) is a substantial global health burden, with treatment outcomes significantly influenced by the interaction between the immune system and the tumor microenvironment. OBJECTIVE: This study aims to investigate the role of peripheral blood immune cell subpopulations, particularly CD8+ CD28+ T cells, in predicting treatment response in metastatic CRC patients receiving bevacizumab combined with chemotherapy. METHODS: A cohort of 45 CRC patients was analyzed. Flow cytometry was utilized to assess immune cell subpopulations. RESULTS: Higher CD8+ CD28+ T cell counts were associated with better treatment responses, including improved objective response rates. In a murine CRC model, the combination therapy significantly inhibited tumor growth and enhanced immune cell function. CONCLUSION: These findings highlight the importance of CD8+ CD28+ T cells as potential biomarkers for predicting treatment outcomes in CRC. They also suggest that bevacizumab, when combined with chemotherapy, can modulate immune function and improve clinical efficacy.