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 mAb 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. Significance: Sialylated cancer IgG activates c-Met-SOX2 signaling to promote stemness properties in cancer cells and can be targeted to suppress tumor growth.

Hepatocellular carcinoma (HCC) is characterized by a high rate of incidence and recurrence, and resistance to chemotherapy may aggravate the poor prognosis of HCC patients. Sorafenib resistance is a conundrum to the treatment of advanced/recurrent HCC. Therefore, studies on the molecular pathogenesis of HCC and the resistance to sorafenib are of great interest. Here, we report that GINS1 was highly expressed in HCC tumors, associated with tumor grades, and predicted poor patient survival using Gene Expression Omnibus (GEO) databases exploration. Cell cycle, cell proliferation assay and in vivo xenograft mouse model indicated that knocking down GINS1 induced in G1/S phase cell cycle arrest and decreased tumor cells proliferation in vitro and in vivo. Spheroid formation assay results showed that GINS1 promoted the stem cell activity of HCC tumor cells. Furthermore, GEO database (GSE17112) analysis showed that HRAS oncogenic gene set was enriched in GINS1 high-expressed cancer cells, and quantitative real-time PCR, and Western blot results proved that GINS1 enhanced HCC progression through regulating HRAS signaling pathway. Moreover, knocking down endogenous GINS1 with shGINS1 increased the sensitivity of HCC cells to sorafenib, and restoring HRAS or stem associated pathway partly recovered the sorafenib resistance. Overall, the collective findings highlight GINS1 functions in hepatocarcinogenesis and sorafenib resistance, and indicate its potential use of GINS1 in drug-resistant HCC.

Immunoglobulin (Ig) is known as a hallmark of B-lymphocytes exerting antibody functions. However, our previous studies demonstrated that myeloblasts from acute myeloid leukemia (AML) patients could also express Ig with distinct roles. Here, we quantified Ig (IGHG and IGK) transcripts by real-time PCR and performed a comprehensive analysis of Ig repertoire (both heavy chains and light chains) in AML blasts. We found that Ig was frequently expressed by AML blasts. A higher level of AML-derived IGHG expression correlated with a significantly shorter disease-free survival. Next-generation sequencing revealed dysregulated transcripts of all five Ig classes (IGHA, IGHD, IGHE, IGHG, and IGHM) and two Ig types (IGK and IGL) in AML. V_H-D-J_H rearrangements in myeloblasts were biased with individual specificity rather than generally diverse as in B-cells. Compared to AML-derived IgH, AML-derived IGK was more conserved among different AML samples. The frequently shared Vκ-Jκ patterns were IGKV3-20*01/IGKJ1*01, IGKV2D-28*01/IGKJ1*01, and IGKV4-1*01/IGKJ1*01. Moreover, AML-derived IGK was different from classical IGK in B-cells for the high mutation rates and special mutation hotspots at serine codons. Findings of the distinct Ig repertoire in myeloblasts may facilitate the discovery of a new molecular marker for disease monitoring and target therapy.

Triple-negative breast cancer (TNBC) is among the most aggressive and lethal subtypes of breast cancer. To date, there are no effective targeted treatment targets. Sialylated IgG (SIA-IgG), with unique sialylated modifications for N-glycosylation at site 162 of the heavy chain of IgG, which was found to be expressed in a variety of cancer cells as a novel procancer factor. Here, we aimed to investigate the expression frequency and procancer mechanisms of SIA-IgG in TNBC, and determine whether the SIA-IgG is a key factor that promotes TNBC and a novel target for TNBC therapy. Immunohistochemical staining, immunofluorescence, and TCGA database analysis were performed to analyze the frequency of SIA-IgG expression in TNBC and the correlation between SIA-IgG expression and patient prognosis. Colony formation, transwell, and Matrigel-transwell assays were used to assess the proliferative and invasive abilities of SIA-IgG. Proteomic mass spectrometry and immunoprecipitation were utilized to identify the key procancer mechanisms of SIA-IgG. Oxygen consumption and extracellular acidification assays were used to elucidate the promotion of glucose metabolism and its mechanism in TNBC. Subcutaneous xenograft models were established to examine the antitumour effects of targeting SIA-IgG. SIA-IgG was frequently detected in TNBC cells and was negatively associated with prognosis. Moreover, exogenously added SIA-IgG significantly enhanced the proliferation, migration and invasion of TNBC cells. Importantly, SIA-IgG significantly promoted TNBC progression by accelerating glycolysis and lactate reuse, which was dependent on its unique N-glycosylation at the Asn162 site. Conversely, the inhibition of SIA-IgG inhibited cancer cell proliferation and invasion by decreasing ATP and lactate production. Knockdown of SIA-IgG, as well as treatment with the anti-SIA-IgG antibody, significantly inhibited TNBC growth in vivo. Mechanistically, SIA-IgG promoted glycolysis and the lactate cycle mainly through the activation of two pathways: the integrin α6β4-FAK-AKT-HIF-1α-MCT4 axis, and the integrin α6β4-CD44-MCT1 axis. These findings suggest that SIA-IgG, by enhancing glycolysis and the lactate cycle, induces metabolic reprogramming and thereby promotes the development of TNBC, making it a promising target for targeted therapy in TNBC.

Hematological malignancies are a diverse group of cancers that originate in the blood and bone marrow and are characterized by the abnormal proliferation and differentiation of hematopoietic cells. Myeloid blasts, which are derived from normal myeloid progenitors, play a central role in these diseases by disrupting hematopoiesis and driving disease progression. In addition, other myeloid cells, including tumor-associated macrophages and myeloid-derived suppressor cells, adapt dynamically to the tumor microenvironment, where they can promote immune evasion and resistance to treatment. This review explores the unique characteristics and pathogenic mechanisms of myeloid blasts, the immunosuppressive roles of myeloid cells, and their complex interactions within the TME. Furthermore, we highlight emerging therapeutic approaches targeting myeloid cells, focusing on strategies to reprogram their functions, inhibit their suppressive effects, or eliminate pathological populations altogether, as well as the latest preclinical and clinical trials advancing these approaches. By integrating insights from these studies, we aim to provide a comprehensive understanding of the roles of myeloid cells in hematological malignancies and their potential as therapeutic targets.