Calreticulin (CALR) is an endoplasmic reticulum (ER)-resident protein involved in a spectrum of cellular processes. In healthy cells, CALR operates as a chaperone and Ca2+ buffer to assist correct protein folding within the ER. Besides favoring the maintenance of cellular proteostasis, these cell-intrinsic CALR functions support Ca2+-dependent processes, such as adhesion and integrin signaling, and ensure normal antigen presentation on MHC Class I molecules. Moreover, cancer cells succumbing to immunogenic cell death (ICD) expose CALR on their surface, which promotes the uptake of cell corpses by professional phagocytes and ultimately supports the initiation of anticancer immunity. Thus, loss-of-function CALR mutations promote oncogenesis not only as they impair cellular homeostasis in healthy cells, but also as they compromise natural and therapy-driven immunosurveillance. However, the prognostic impact of total or membrane-exposed CALR levels appears to vary considerably with cancer type. For instance, while genetic CALR defects promote pre-neoplastic myeloproliferation, patients with myeloproliferative neoplasms bearing CALR mutations often experience improved overall survival as compared to patients bearing wild-type CALR. Here, we discuss the context-dependent impact of CALR on malignant transformation, tumor progression and response to cancer therapy.

Caryl and Israel Englander Institute for Precision Medicine New York NY USA

Department of Dermatology Yale University School of Medicine New Haven CT USA

Department of Immunology Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Radiation Oncology Weill Cornell Medical College New York NY USA

Equipe labellisée par la Ligue contre le cancer Centre de Recherche des Cordeliers INSERM U1138 Université de Paris Sorbonne Université Paris France

Karolinska Institute Deparment of Women's and Children's Health Karolinska University Hospital Stockholm Sweden

Metabolomics and Cell Biology Platforms Institut Gustave Roussy Villejuif France

Pôle de Biologie Hôpital Européen Georges Pompidou AP HP Paris France

Sandra and Edward Meyer Cancer Center New York NY USA

Sotio Prague Czech Republic

Suzhou Institute for Systems Medicine Chinese Academy of Sciences Suzhou Jiangsu China

Université de Paris Paris France

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