Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation.Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both in vitro and in vivo.However,whether SHP099-mediated SHP2 inhibition retards tumor growth in vivo via anti-tumor immunity remains elusive.To address this,a CT-26 colon cancer xenograft model was established in mice since this cell line is insensitive to SHP099.Consequently,SHP099 minimally affected CT-26 tumor growth in immuno-deficient nude mice,but significantly decreased the tumor burden in CT-26 tumor-beating mice with intact immune system.SHP099 augmented anti-tumor immunity,as shown by the elevated proportion of CD8+IFN-γ+ T cells and the upregulation of cytotoxic T-cell related genes including Granzyme B andPerforin,which decreased the tumor load.In addition,tumor growth in mice with SHP2-deficient T-cells was markedly slowed down because of enhanced anti-tumor responses.Finally,the combination of SHP099 and antiPD-1 antibody showed a higher therapeutic efficacy than either monotherapy in controlling tumor growth in two colon cancer xenograft models,indicating that these agents complement each other.Our study suggests that SHP2 inhibitor SHP099 is a promising candidate drug for cancer immunotherapy.