癌细胞中升高的IgG表达因素可能导致恶性癌症加重和不良临床预后。越来越多的证据表明非常规唾液酸化修饰对癌症来源的IgG的功能至关重要，表明需要更好地了解调节唾液酸化癌症IgG（SIA-cIgG）表达和功能的调节机制。在这里，我们进行了全基因组CRISPR活化筛选，并确定OCT4和SOX2是促进SIA-cIgG表达的关键因素。功能研究揭示了SIA-cIgG通过激活c-Met / Akt / Erk信号通路，与SOX2相互刺激，构成了SIA-cIgG / c-Met / SOX2 / SIA-cIgG信号的自我传播循环。这种信号循环在许多上皮癌症的干细胞中高度活跃，对体外和体内的肿瘤干性至关重要。值得注意的是，特异性识别SIA-cIgG上Asn162唾液酸化相关表位的单克隆抗体RP215有效阻止了SIA-cIgG驱动的信号循环。此外，RP215在基于患者的异种移植模型中显著抑制了肺癌细胞的干性和肿瘤生长。总之，这些发现揭示了一个自我传播的c-Met / SOX2 / SIA-cIgG信号循环，促进了癌症干细胞性，为癌症治疗提供了新的治疗策略。

Elevated IgG expression in cancer cells has been implicated in exacerbated malignancy and poor clinical prognosis. Accumulating evidence indicates that a nonconventional sialylation modification is critical for the function of cancer-derived IgG, indicating the need for a better understanding of the regulatory mechanisms that control the expression and function of sialylated cancer IgG (SIA-cIgG). Here, we conducted genome-wide CRISPR activation screening and identified OCT4 and SOX2 as the key factors that promote SIA-cIgG expression. Functional investigation revealed that SIA-cIgG reciprocally stimulated SOX2 by activating the c-Met/Akt/Erk signaling axis, constituting a self-propagating loop of SIA-cIgG/c-Met/SOX2/SIA-cIgG signaling. This signaling loop was highly active in stem-like cells from many epithelial cancers and was crucial for cancer stemness in vitro and in vivo. Notably, the monoclonal antibody RP215, which specifically recognizes the Asn162 sialylation-related epitope on SIA-cIgG, effectively blocked the SIA-cIgG-driven signaling loop. Furthermore, RP215 significantly inhibited lung cancer cell stemness and tumor growth in a patient-derived xenograft model. In conclusion, these findings revealed a self-propagating c-Met/SOX2/SIA-cIgG signaling loop that promotes cancer stemness, identifying novel therapeutic strategies for cancer treatment.