It is still enigmatic under which circumstances cellular demise induces an immune response or rather remains immunologically silent. Moreover, the question remains open under which circumstances apoptotic, autophagic or necrotic cells are immunogenic or tolerogenic. Although apoptosis appears to be morphologically homogenous, recent evidence suggests that the pre-apoptotic surface-exposure of
calreticulin may dictate the immune response to
tumor cells that succumb to anticancer treatments. Moreover, the release of high-mobility group box 1 (
HMGB1) during late apoptosis and secondary
necrosis contributes to efficient antigen presentation and cytotoxic T-cell activation because
HMGB1 can bind to
Toll like receptor 4 on dendritic cells, thereby stimulating optimal antigen processing. Cell death accompanied by autophagy also may facilitate cross priming events. Apoptosis,
necrosis and autophagy are closely intertwined processes. Often, cells manifest autophagy before they undergo apoptosis or
necrosis, and apoptosis is generally followed by secondary
necrosis. Whereas apoptosis and
necrosis irreversibly lead to cell death, autophagy can clear cells from stress factors and thus facilitate cellular survival. We surmise that the response to cellular stress like
chemotherapy or ionizing irradiation, dictates the immunological response to dying cells and that this immune response in turn determines the clinical outcome of anticancer
therapies. The purpose of this review is to summarize recent insights into the immunogenicity of dying
tumor cells as a function of the cell death modality.