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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.