Treatment of HER2/neu-overexpressing target cells with interferon gamma (IFN gamma) (200-2000 U/ml for 3 days) markedly enhances their sensitivity to lymphokine-activated killer (LAK) cell lysis. Increased sensitivity is associated with an up-regulation of intercellular adhesion molecule ICAM-1 determinants and a down-regulation of HER2/neu expression. In the present study, we show that exposure to another cytokine, tumor necrosis factor alpha (200 U/ml for 3 days), also decreased HER2/neu expression but had no effect on LAK cell lysis and ICAM-1 expression. This suggests that down-regulation of oncogene expression is not sufficient by itself to induce an enhanced sensitivity to LAK cell lysis. IFN-induced enhanced lysis was associated with an increased binding between effectors and targets, and antibodies to ICAM-1 as well as its counter-receptor LFA-1, blocked the increased binding and lysis. Treatment with IFN gamma still significantly enhanced lysis even when concanavalin A was added to the assay to induce maximal binding, indicating that a post-binding effect also participated in enhanced cytotoxicity. These post-binding alterations, were also sensitive to blocking with anti-ICAM-1 and anti-LFA-1 antibodies. Treatment with IFN also sensitized targets to lysis by T cells in the presence of lectin but had no effect on the relative resistance of HER2+ cells to lysis mediated by perforin or TNF. Together these data demonstrate the importance of ICAM-1 determinants in binding and post-binding events in the IFN-induced increased lysis of HER2/neu+ targets.