Doxorubicin-induced tumor cell death can elicit an effective antitumor immune response, even in the absence of adjuvants. This study shows that anthracyclins, such as doxorubicin (DX), induce immunogenic cell death, which leads to the suppression of tumor growth or regression of established tumors. While both anthracyclins and mitomycin C (MC) induce apoptosis with caspase activation, only anthracyclins induce immunogenic cell death. Inhibiting caspases with Z-VAD-fmk or p35 reduced the immunogenicity of DX-treated cells in several models. Dendritic cells (DCs) and CD8+ T cells were essential for the immune response against DX-treated apoptotic tumor cells. Freshly excised tumors became immunogenic upon DX treatment in vitro, and intratumoral DX could trigger regression of established tumors in immunocompetent mice. These findings suggest a method for generating cancer vaccines and stimulating anti-tumor immune responses in vivo. The study highlights the importance of caspase activation in the immunogenicity of DX-treated tumor cells. DX-induced apoptosis is more immunogenic than MC-induced apoptosis, as evidenced by the ability of DX-treated cells to elicit a stronger immune response. The presence of DX in the cells is crucial for immunogenicity, and the mode of cell death, rather than the presence of DX itself, determines immunogenicity. DX-treated cells are efficiently phagocytosed by DCs and induce DC maturation, leading to the activation of CD8+ T cells. The immune response is dependent on the presence of DCs and CD8+ T cells, and NK cells are not required for the antitumor immune response. The study also shows that DX can induce immunogenic cell death in various tumor models, including melanoma and colon carcinoma. Ex vivo treatment of tumors with DX can generate immunogenic cells that confer protection against tumor growth. Intratumoral injection of DX can lead to stable disease or complete tumor regression in some animals. However, the effectiveness of DX treatment varies among individuals, and the immune system plays a crucial role in the therapeutic response. The findings suggest that caspase activation is essential for the immunogenicity of DX-treated tumor cells, and that the chemical nature of anthracyclins is not the sole determinant of immunogenicity. The study provides a framework for the development of immunogenic cancer therapies and highlights the importance of caspase activation in the immune response to tumor cells.Doxorubicin-induced tumor cell death can elicit an effective antitumor immune response, even in the absence of adjuvants. This study shows that anthracyclins, such as doxorubicin (DX), induce immunogenic cell death, which leads to the suppression of tumor growth or regression of established tumors. While both anthracyclins and mitomycin C (MC) induce apoptosis with caspase activation, only anthracyclins induce immunogenic cell death. Inhibiting caspases with Z-VAD-fmk or p35 reduced the immunogenicity of DX-treated cells in several models. Dendritic cells (DCs) and CD8+ T cells were essential for the immune response against DX-treated apoptotic tumor cells. Freshly excised tumors became immunogenic upon DX treatment in vitro, and intratumoral DX could trigger regression of established tumors in immunocompetent mice. These findings suggest a method for generating cancer vaccines and stimulating anti-tumor immune responses in vivo. The study highlights the importance of caspase activation in the immunogenicity of DX-treated tumor cells. DX-induced apoptosis is more immunogenic than MC-induced apoptosis, as evidenced by the ability of DX-treated cells to elicit a stronger immune response. The presence of DX in the cells is crucial for immunogenicity, and the mode of cell death, rather than the presence of DX itself, determines immunogenicity. DX-treated cells are efficiently phagocytosed by DCs and induce DC maturation, leading to the activation of CD8+ T cells. The immune response is dependent on the presence of DCs and CD8+ T cells, and NK cells are not required for the antitumor immune response. The study also shows that DX can induce immunogenic cell death in various tumor models, including melanoma and colon carcinoma. Ex vivo treatment of tumors with DX can generate immunogenic cells that confer protection against tumor growth. Intratumoral injection of DX can lead to stable disease or complete tumor regression in some animals. However, the effectiveness of DX treatment varies among individuals, and the immune system plays a crucial role in the therapeutic response. The findings suggest that caspase activation is essential for the immunogenicity of DX-treated tumor cells, and that the chemical nature of anthracyclins is not the sole determinant of immunogenicity. The study provides a framework for the development of immunogenic cancer therapies and highlights the importance of caspase activation in the immune response to tumor cells.