The way by which conventional chemotherapy kills tumor cells has long been known as a direct tumoricidal effect. Nevertheless, it is assumed that tumor cell death can elicit an immune response by emitting danger signals to dendritic cells (DCs) infiltrating in the tumor. A newly published paper in Nature Medicine (2007, 13:1050-1058) by Apetoh et al. revealed that the Toll-like receptor 4 (TLR4) expressed on DCs plays a critical role for the activation of antigen-specific T-cell immunity. The authors demonstrated that in mice, wild-type or lacking different TLRs, inoculated with doxorubicin-or oxaliplatin-treated dying tumor cells into the foot pad, only the Tlr4-/- mice were defective in T-cell priming (measured as IFN-γproduction) after re-stimulation with tumor antigen. If DCs were depleted in wild-type mice, the priming of T cells by dying tumor was abrogated. They then used co-precipitation assays to show that the endogenous high-mobility group box 1 protein (HMGB1) is released by dying tumor cells and constitutes a danger signal that mobilizes the immune response by binding and stimulating TRLA on DCs. After recognition of HMGB1, TLR4 transduces signals through the TLR adaptor myeloid differentiation primary response protein (MYD88), as Myd88-/- DCs behaved in the same way as Tlr4-/- DCs when exposed to dying tumor cells. Tlr4-/- mice, or dying tumor cells lacking HMGB1, could not trigger an effective anti-tumor response against the same tumor inoculated one week after the initial injection. If mice with established tumors lacking TLR4 or MYD88, chemotherapy was not as effective at reducing tumor growth or prolonging survival as in wild-type mice. The clinical relevance of these findings was demonstrated in breast cancer patients. About 8% -10% Caucasians have a polymorphism in TLR4 (Asp299Gly) , which could compromise the effectiveness of chemotherapy in breast cancer patients. The authors found that this polymorphism reduced the interaction between TLR4 and HMGB1, and prevented DCs from presenting antigen to cytotoxic T cells. They analyzed the time to metastasis in 280 patients with non-metastatic breast cancer who had been treated with anthracyclines after surgery because of lymph node involvement. The frequency of metastasis by 5 years after surgery was 40% in those with mutant TLR4, compared to 26.5% in patients with wild-type TLR4, and the metastasis-free survival of patients with mutant TLR4 was also significantly lower. Dying tumor cells therefore elicit an immune response that is required for the success of chemotherapy. The way by which conventional chemotherapy kills tumor cells has long been known as a direct tumoricidal effect. Nevertheless, it is assumed that tumor cell death can elicit an immune response by emitting danger signals to dendritic cells (DCs) infiltrating in the tumor. A newly published paper in Nature Medicine (2007, 13: 1050-1058) by Apetoh et al. revealed that the Toll-like receptor 4 (TLR4) expressed on DCs plays a critical role for the activation of antigen-specific T-cell immunity. authors said that in mice, wild-type or lacking different TLRs, inoculated with doxorubicin-or oxaliplatin-treated dying tumor cells into the foot pad, only the Tlr4 - / - mice were defective in T-cell priming (measured as IFN- γproduction If DCs were depleted in wild-type mice, the priming of T cells by dying tumor was abrogated. They then used co-precipitation assays to show that the endogenous high-mobility group box 1 protein ( HMGB1) is released b y dying tumor cells and constitutes a danger signal that mobilizes the immune response by binding and stimulating TRLA on DCs. After recognition of HMGB1, TLR4 transduces signals through the TLR adapter myeloid differentiation primary response protein (MYD88), as Myd88 - / - DCs behaved in the same way as Tlr4 - / - DCs when exposed to dying tumor cells. Tlr4 - / - mice, or dying tumor cells lacking HMGB1 could not trigger an effective anti-tumor response in the same tumor inoculated one week after the initial injection . If mice with established tumors lacking TLR4 or MYD88, chemotherapy was not as effective at reducing tumor growth or prolonging survival as in wild-type mice. The clinical relevance of these findings was demonstrated in breast cancer patients. About 8% -10% Caucasians have a polymorphism in TLR4 (Asp299Gly), which could compromise the effectiveness of chemotherapy in breast cancer patients. The authors found that this polymorphism reduced the interaction between TLR4 andHMGB1, and prevented DCs from presenting antigen to cytotoxic T cells. They analyzed the time to metastasis in 280 patients with non-metastatic breast cancer who had been treated with anthracyclines after surgery because of lymph node involvement. The frequency of metastasis by 5 years after surgery was 40% in those with mutant TLR4, compared to 26.5% in patients with wild-type TLR4, and the metastasis-free survival of patients with mutant TLR4 was also significantly lower. Dying tumor cells therefore elicit an immune response that is required for the success of chemotherapy.