Metabolic reprogramming is a feature of cancer cells and crucial for tumor growth and metastasis. Interferon-gamma (IFN gamma) is a cytokine that plays a pivotal role in host antitumor immunity. However, little is known about the roles of metabolic reprogramming in immune responses. Here, we show that colon cancer cells reprogram metabolism to coordinate proper cellular responses to IFN gamma by downregulating mitochondrial pyruvate carrier (MPC)1 and 2 via STAT3 signaling. Forced overexpression of MPC promote the production of reactive oxygen species and enhance the apoptosis induced by IFN gamma in colon cancer cells. Moreover, inhibiting STAT3 sensitize the antitumor efficacy of IFN-gamma against colon cancer cells. Our findings present a previously unrecognized mechanism that colon cancer manipulate to resist IFN gamma mediated antitumor immunity that have implications for targeting a unique aspect of this disease.