Impressive inhibition of tumor growth has been observed after transduction of cytokine genes into tumor cells. Secreted cytokines do not affect the proliferation of a tumor directly but activate a host immune reaction strong enough to overcome its oncogenic capacity. However, the reaction mechanisms activated are difficult to interpret; because these mechanisms have been derived from experiments with different tumors, comparisons are hindered. To compare the reactive mechanisms induced by each cytokine, BALB/c mice were challenged with the parental cells of the syngeneic spontaneous mammary adenocarcinoma TSA, or with TSA cells engineered to release IL2, IL4, IL7, IL10, IFN alpha, IFN gamma, and TNF alpha, and the tumor growth area was studied histologically, ultrastructurally, and immunohistochemically. These observations were integrated with data on the growth and rejection patterns of TSA cells in mice depleted of natural killer (NK) cells, granulocytes, CD4+, or CD8+ lymphocytes. The rejection of TSA-IL2 and TSA-TNF alpha cells was associated with the massive presence of neutrophils, that of TSA-IL4 and TSA-IL7 cells with neutrophils and very small areas of colliquative necrosis, and that of TSA-IFN alpha and TSA-IL10 cells with extensive areas of ischemic-coagulative necrosis and some neutrophils. TSA-IFN gamma cells displayed a delay in growth, but were not rejected. Their growth areas comprised necrotic zones of ischemic necrosis devoid of neutrophils. The selective depletion experiments demonstrated that rejection of engineered TSA cells depends on several leukocyte populations. The weight of each population varied with the secreted cytokine, although neutrophils and CD8+ lymphocytes constantly played the major role. Employment of the same tumor line engineered with the genes of different cytokines showed that each cytokine evokes a distinct reaction and that tumor inhibition results from a complex mechanism in which neutrophils and CD8+ lymphocytes and ischemic necrosis are of primary importance.