Autophagy mediated danger signaling regulates tumor immunosurveillance and may potentiate the effects of anti-cancer immunotherapy through increased adjuvanticity

Autophagy has a multifaceted role in cancer, and a growing body of evidence demonstrates a central role for autophagy in modulating adjuvanticity, which is essential for natural and therapy-induced immunosurveillance. Adjuvanticity in this context is conferred by the release of specific damage associated molecular patterns (DAMPs) from dying cancer cells acting as adjuvants communicating the state of danger to the tumor microenvironment and host. High pre-mortem autophagy has been linked to the increased release of DAMPs, which act as immunoadjuvant signals in the tumor microenvironment and exert their effect by bridging innate and adaptive arms of the immune system. Together with the immunogenicity of cancers, it is evident that proper adjuvanticity is required for a robust initiation of the cancer immunity cycle, and several clinical trial protocols are currently exploring the potential clinical benefit of increasing adjuvanticity in the context of immune checkpoint inhibitor (ICI) treatment regimens. While this is an appealing strategy, the research field is still in its infancy, and due to several experimental limitations, which will be discussed in detail here, the exact role of autophagy in these processes is still obscure. Here, we aim to review the current understanding regarding the role of autophagy in shaping tumor immunogenicity, the interdependent regulatory relationship between autophagy and DAMPs, and how this might be explored as a therapeutic strategy to “heat up” so-called immune “cold” tumors. Much is yet to be learned regarding how targeting autophagy might shift the polarization of immune cell phenotypes in a manner that might either support or repress anti-tumor immunity. Improved methodology, increased knowledge, and more specific inhibitors of autophagy will ultimately allow for the rational design of clinical trials where autophagy is being rigorously tested as a target for therapeutic benefit in cancer therapy.