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.

钙网蛋白 (CALR) 是一种内质网 (ER) 驻留蛋白，参与一系列细胞过程。在健康细胞中，CALR 充当分子伴侣和 Ca ²⁺缓冲液，以帮助内质网内正确的蛋白质折叠。除了有利于维持细胞蛋白质稳态外，这些细胞内在 CALR 功能还支持 Ca ²⁺依赖性过程，例如粘附和整合素信号传导，并确保 MHC I 类分子上的正常抗原呈递。此外，死于免疫原性细胞死亡 (ICD) 的癌细胞会在其表面暴露 CALR，从而促进专业吞噬细胞对细胞尸体的吸收，并最终支持抗癌免疫的启动。因此，功能丧失的 CALR突变促进肿瘤发生不仅因为它们损害健康细胞的细胞稳态，而且因为它们损害自然和治疗驱动的免疫监视。然而，总的或膜暴露的 CALR 水平的预后影响似乎因癌症类型而异。例如，虽然遗传性CALR缺陷会促进肿瘤前骨髓增殖，但与携带野生型CALR 的患者相比，携带CALR突变的骨髓增殖性肿瘤患者的总体生存率通常有所提高。在这里，我们讨论了 CALR 对恶性转化、肿瘤进展和对癌症治疗的反应的上下文相关影响。