Lymphocytes recovered from human tumors or the peripheral blood of patients with advanced malignancies are functionally compromised. Abnormalities in signaling via the T cell receptor (TcR) in T cells and Fc gamma RIII in NK cells obtained from cancer patients include significantly decreased expression of the receptor-associated zeta chains, decreased Ca++ flux as well as impaired kinase activity following triggering with anti-CD3 or anti-CD16 antibodies, respectively, and altered expression of downstream protein tyrosine kinase p56lck. Some of these defects were demonstrable in situ, in T cells infiltrating tumor tissues. Post-translational modifications of the zeta protein were responsible for its low levels, since near normal levels of mRNA were present in situ in the patients' T cells. LNL in tumor-involved LN or mononuclear cells in solid tumors were shown to contain numerous apoptotic (TUNEL+) CD3+ lymphocytes. Co-incubation of normal activated T cells or Jurkat cells with tumor targets (either freshly isolated or tumor cell lines) induced degradation of the zeta chain as well as apoptosis in a proportion of lymphocytes. Both fresh and cultured human tumors were shown to express FasL, and T cells in tumors were found to be Fas+. Therefore, the Fas-FasL pathway is, at least in part, responsible for signaling defects and apoptosis induced by the tumor in lymphocytes found in its milieu. Preliminary data indicate that immunotherapy with cytokines might normalize zeta expression in T cells and partly restore their antitumor functions.