Autophagy, a virtually uniform response to external stress such as that induced by chemotherapy and radiation, is generally considered to be cytoprotective in function, providing a foundation for multiple clinical trials designed to enhance therapeutic response via autophagy inhibition. However, this cell autonomous response can also be cytotoxic or nonprotective, with the consequence that autophagy inhibition would be counterproductive or ineffective, respectively. The non-cell autonomous function of autophagy remains quite controversial, with evidence both for and against autophagy-mediated activation of the immune system. If autophagy inhibition antagonizes the immune response, this would likely interfere with the potential sensitization resulting from suppression of the cell autonomous protective function. An additional complication, which has rarely been considered, is the nature of the contribution of therapy-induced autophagy in the tumor microenvironment, particularly the tumor stroma. Taken together, it is likely that the outcome of the current clinical trials, whether positive or negative, will be difficult to interpret given the complexity of the role of autophagy relating to the tumor cell (cell autonomous), the immune system (cell non-autonomous) and the tumor microenvironment.
Keywords: Autophagic cell death; Autophagy; Chemotherapy; Danger associated molecular pattern; Immunogenic cell death; Radiation therapy.
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