T-lymphocytes (LYs) from normal and IFN-γ knockout mice were activated by anti-CD3 and anti-CD28 antibodies and cultured in inserts in the presence of interleukin (IL)-12 (IL-12-activated LYs) or not (activated LYs). Their ability to modulate the genetic programs of two tumor lines growing at the bottom of transwells was evaluated. cDNA gene expression array, reverse transcription-PCR, and protein expression showed that LPS, transcription termination factor 1, transforming growth factor, and fibroblast growth factor genes were up-modulated by factors other than IFN-γ released by activated LYs. The high levels of IFN-γ released by normal IL-12-activated LYs up-modulated the expression of STAT1, IRF-1, LMP2, LMP7, monokine induced by IFN-γ, monocyte chemoattractant protein 1, and angiopoietin 2 genes but down-modulated the expression of vascular endothelial growth factor. PA28, IFN-inducible protein 10, inducible NO synthetase, and macrophage-inhibitory protein 2 genes were up-modulated by factors released only by IL-12-activated LYs apart from IFN-γ. The opposite modulations of vascular endothelial growth factor expression and of angiopoietin 2, monokine induced by IFN-γ, IFN-inducible protein 10, and inducible NO synthetase by IL-12-activated LYs fit in well with the inhibition of angiogenesis that characterizes the antitumor activity of IL-12. T-LYs thus modify a tumor’s behavior so that it becomes a party to its own inhibition.