Immunotherapy induces durable clinical responses in a fraction of patients with cancer. However, therapeutic resistance poses a major challenge to current immunotherapies. Here, we identify that expression of tumor stanniocalcin 1 (STC1) correlates with immunotherapy efficacy and is negatively associated with patient survival across diverse cancer types. Gain- and loss-of-function experiments demonstrate that tumor STC1 supports tumor progression and enables tumor resistance to checkpoint blockade in murine tumor models. Mechanistically, tumor STC1 interacts with calreticulin (CRT), an “eat-me” signal, and minimizes CRT membrane exposure, thereby abrogating membrane CRT-directed phagocytosis by antigen-presenting cells (APCs), including macrophages and dendritic cells. Consequently, this impairs APC capacity of antigen presentation and T cell activation. Thus, tumor STC1 inhibits APC phagocytosis and contributes to tumor immune evasion and immunotherapy resistance. We suggest that STC1 is a previously unappreciated phagocytosis checkpoint and targeting STC1 and its interaction with CRT may sensitize to cancer immunotherapy.

免疫疗法在一小部分癌症患者中诱导持久的临床反应。然而，治疗耐药性对当前的免疫疗法构成了重大挑战。在这里，我们确定了肿瘤斯钙素 1（STC1) 与免疫治疗效果相关，并且与不同癌症类型的患者存活率呈负相关。功能增益和功能丧失实验表明，肿瘤 STC1 支持肿瘤进展并使肿瘤对小鼠肿瘤模型中的检查点阻断产生抗性。从机制上讲，肿瘤 STC1 与钙网蛋白 (CRT)（一种“吃我”信号）相互作用，并最大限度地减少 CRT 膜暴露，从而消除包括巨噬细胞和树突状细胞在内的抗原呈递细胞 (APC) 对膜 CRT 指导的吞噬作用。因此，这会削弱 APC 抗原呈递和 T 细胞活化的能力。因此，肿瘤STC1抑制APC吞噬作用并有助于肿瘤免疫逃避和免疫治疗抵抗。