T cells can kill tumors more effectively if a roadblock in their receptor signaling is removed, report Loeser et al. on page 879. Figure 1 Mice that lack cbl-b spontaneously reject UV-induced tumors. Most tumors are poor targets for the immune system as they frequently lack costimulatory molecules and present antigens that are only weakly immunogenic. The few tumor-specific T cells that do get generated are tolerized and fail to see the tumor as a dangerous enemy. Strategies to induce strong antitumor T cell responses—including cytokine treatment to coax tumors into expressing costimulatory proteins or vaccination with host dendritic cells loaded with tumor antigens—have not always worked. Loeser and colleagues decided instead to circumvent tolerogenic mechanisms within the antitumor T cells themselves. Their target was the ubiquitin ligase cbl-b, which inhibits TCR signals by targeting downstream signaling proteins for proteasomal degradation. The group had previously shown that T cells lacking cbl-b are efficiently activated by weak antigens even in the absence of costimulation, suggesting that cbl-b functioned as an internal tolerance enforcer. They now find that these T cells are efficient tumor killers as well. Mice lacking cbl-b were able to spontaneously reject tumors that were either injected into the animals or induced by UV exposure. Cbl-b–deficient CD8+ T cells destroyed tumors when transferred into wild-type animals. These cells developed into memory cells and offered long-lasting protection against tumor recurrence. One pitfall of removing a tolerogenic T cell protein such as cbl-b is the threat of autoimmunity. The cbl-b–deficient mice do show signs of autoimmune damage. However, these side effects are not lethal, and the mice have a normal lifespan. The team now plans to test whether antitumor T cell activity in mice can be mediated by RNAi knock-down of cbl-b, as this strategy may be practical in humans.