Tyrosine phosphatase SHP2 is really a promising drug target in cancer immunotherapy because of its bidirectional role both in tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 may hinder cancer cell growth in vitro as well as in vivo. However, whether SHP099-mediated SHP2 inhibition retards tumor development in vivo via anti-tumor immunity remains elusive. To deal with this, a CT-26 cancer of the colon xenograft model started in rodents because this cell lines are insensitive to SHP099. Consequently, SHP099 minimally affected CT-26 tumor development in immuno-deficient nude rodents, but considerably decreased the tumor burden in CT-26 tumor-bearing rodents with intact defense mechanisms. SHP099 augmented anti-tumor immunity, as proven through the elevated proportion of CD8 IFN-γ T cells and also the upregulation of cytotoxic T-cell related genes including Granzyme B andPerforin, which decreased the tumor load. Additionally, tumor development in rodents with SHP2-deficient T-cells was markedly slowed lower due to enhanced anti-tumor responses. Finally, the mixture of SHP099 and anti-PD-1 antibody demonstrated a greater therapeutic effectiveness than either monotherapy in managing tumor development in two cancer of the colon xenograft models, indicating these agents complement one another. Our study shows that SHP2 inhibitor SHP099 is really a promising candidate drug for cancer immunotherapy.