In this study, we identified a threshold for “danger discrimination” in macrophages after sensing specific changes in protein expression at the surface of cells with an advanced premalignant phenotype. The identification of these “danger signals” could stimulate the development of novel targeted chemoprevention and immunoprophylactic strategies. Drugs could also be developed to lower the discrimination threshold and therefore eliminate more efficiently earlier stages of premalignacy. Besides the applications for cancer prevention, a better understanding of mechanisms selected for immune tolerance could also have implications for the management of auto-immune disorders.