ABSTRACT Implantation of tumor cells modified by in vitro cytokine gene transfer has been shown by many investi- gatorstoresultinpotentinvivoantitumoractivitiesinmice. Here we describe an approach to tumor immunotherapy utilizing direct transfection of cytokine genes into tumor- bearing animals by particle-mediated gene transfer. In vivo transfectionofthehuman interleukin6geneintothetumor site reduced methylcholanthrene-induced fibrosarcoma growth,andacombinationofmurinetumornecrosisfactora and interferon y genes inhibited growth of a renal carcinoma tumor model (Renca). In addition, treatment with murine interleukin2andinterferon-ygenesprolongedthesurvivalof Renca tumor-bearing mice and resulted in tumor eradication in 25% of the test animals. Transgene expression was dem- onstratedintreatedtissuesbyELISAandimmunohistochem- ical analysis. Significant serum levels of interleukin 6 and interferon y were detected, demonstrating effective secretion oftransgenicproteinsfromtreatedskinintothebloodstream. Thisinvivocytokinegenetherapyapproachprovidesasystem forevaluatingtheantitumorpropertiesofvariouscytokinesin different tumor models and has potential utility for human cancer gene therapy.