Many stage I-III cancers have spawned clinically undetectable metastatic colonies even prior to diagnosis and surgical removal of the primary tumor. It is eventual outgrowth of these microscopic lesions that causes metastatic relapse and death, yet events that dictate when and how disseminated cells convert to overt metastases are largely unknown. Suppression of immune function within the tumor microenvironment is a recognized phenomenon during tumor progression; however, the mechanisms by which tumors maintain immune suppression during systemic metastasis remain enigmatic. Our data implicate the Ron receptor tyrosine kinase pathway as a key mediator of CD8+ T cell suppression during conversion of micro-metastases to bona fide metastatic lesions. Loss of Ron function through genetic manipulation or pharmacological inhibition allows an effective anti-tumor CD8+ T cell response, specifically inhibiting outgrowth of seeded metastatic tumor colonies. Our findings unveil a new therapeutic opportunity for preventing outgrowth of micro-metastases in cancer patients, thus potentially reducing cancer mortality.