A poorly immunogenic murine colon cancer was used to investigate mechanisms of antitumor immunity. Injection of tumor cells engineered by gene transfection to secrete IL-2 stimulated an MHC class l-restricted cytolytic T lymphocyte (CTL) response against the parental tumor. The tumor cells secreting IL-2 produced an antitumor response in vivo, even in the absence of CD4+ T cells. Animals immunized with the engineered cells were protected against subsequent challenge with the parental tumor cell line. Similar findings were demonstrated for other tumor types. Thus, provision of a helper lymphokine in a paracrine fashion induced a tumor-specific immune response involving activation of endogenous CTLs and other immune effector cells. These findings demonstrate that the failure of an effective antitumor immune response may be primarily due to a helper arm deficiency of the immune system rather than a paucity of tumor-specific cytotoxic effector cells. Furthermore, they outline a novel strategy for augmenting tumor immunity.