What is the clinical significance of the expression by common human carcinomas of the Thomsen-Friedenreich (TF) antigen? Described as a terminal disaccharide which is a precursor of MN blood group antigens, it was discovered as a laboratory curiosity 60 years ago, yet its cancer-association has only been appreciated in the last two decades. It is cryptic in the membrane of various normal cells, but can be found overtly expressed early during malignant transformation. It thus has potential as a target antigen for monoclonal antibodies for the detection of cancers, both in vitro and in vivo. Several studies have described its expression in relation to tumor grade, metastasis and likelihood of relapse or tumor aggression, and attempts have been made to define its prognostic significance, but generalization is difficult because of differing trends in expression on different types of cancers. TF is immunogenic, and perhaps even immunomodulatory in patients with cancer. We have used natural and synthetic TF and related antigens to study this immunomodulation in an animal model. Natural TF can be either immunogenic or immunosuppressive. In an appropriate formulation synthetic TF can be used in an 'immunotherapeutic vaccine' to significantly prolong the lives of animals which have an otherwise lethal mammary cancer. We are now testing similar immunotherapeutic vaccines in humans with cancer, and have induced an immune response to synthetic TF, the same serum also reacting with cancer cells known to express TF. The clinical significance of TF may be the immune response it induces, either tolerizing a patient to a cancer or stimulating an effector response to a cancer.(ABSTRACT TRUNCATED AT 250 WORDS)