DAMPening tumor immune escape: the role of ER chaperones in immunogenic chemotherapy.

Preclinical and clinical research in the past two decades has redefined the mechanism of action of some chemotherapeutics that are able to activate the immune system against cancer when cell death is perceived by the immune cells. This immunogenic cell death (ICD) activates antigen-presenting cells (APCs) and T cells to induce immune-mediated tumor clearance. One of the key requirements to achieve this effect is the externalization of the danger-associated molecular patterns (DAMPs), molecules released or exposed by cancer cells during ICD that increase the visibility of the cancer cells by the immune system. In this review, we focus on the role of calreticulin (CRT) and other ER chaperones, such as the heat-shock proteins (HSPs) and the protein disulfide isomerases (PDIs) as surface-exposed DAMPs. Once exposed on the cell membrane, these proteins shift their role from that of ER chaperone and regulator of Ca2+ and protein homeostasis to act as an immunogenic signal for APCs, driving DC-mediated phagocytosis and T-mediated anti-tumor response. However, cancer cells exploit several mechanisms of resistance to immune attack, including subverting the exposure of ER chaperones on their surface to avoid immune recognition. Overcoming these mechanisms of resistance represents a potential therapeutic opportunity to improve cancer treatment effectiveness and patient outcomes.