Early detection significantly correlates with improved survival in cancer patients. So far, a limited number of biomarkers have been validated to diagnose cancers at an early stage. Considering the leading cancer types that contribute to more than 50% of deaths in the USA, we discuss the ongoing endeavors toward early detection of lung, breast, ovarian, colon, prostate, liver, and pancreatic cancers to highlight the significance of mucin glycoproteins in cancer diagnosis. As mucin deregulation is one of the earliest events in most epithelial malignancies following oncogenic transformation, these high-molecular-weight glycoproteins are considered potential candidates for biomarker development. The diagnostic potential of mucins is mainly attributed to their deregulated expression, altered glycosylation, splicing, and ability to induce autoantibodies. Secretory and shed mucins are commonly detected in patients’ sera, body fluids, and tumor biopsies. For instance, CA125, also called MUC16, is one of the biomarkers implemented for the diagnosis of ovarian cancer and is currently being investigated for other malignancies. Similarly, MUC5AC, a secretory mucin, is a potential biomarker for pancreatic cancer. Moreover, anti-mucin autoantibodies and mucin-packaged exosomes have opened new avenues of biomarker development for early cancer diagnosis. In this review, we discuss the diagnostic potential of mucins in epithelial cancers and provide evidence and a rationale for developing a mucin-based biomarker panel for early cancer detection.

Glycosylation controls immune evasion, tumor progression, and metastasis. However, how tumor cell sialylation regulates immune evasion remains poorly characterized. ST6GalNAc-I, a sialyltransferase that conjugates sialic acid to the glycans in glycoproteins, was overexpressed in an aggressive-type KPA ( Kras ^G12D/+ Trp53 ^R172H/+ Ad-Cre ) lung adenocarcinoma (LUAD) model and patient samples. Proteomic and biochemical analysis indicated that ST6GalNAc-I mediated NECTIN2 sialylation in LUAD cells. ST6GalNAc-I–deficient tumor cells cocultured with T cells were more susceptible to T cell–mediated tumor cell killing, indicating a key role for NECTIN2 in T cell dysfunction. Mice injected with St6galnac-I–knockdown syngeneic cells showed reduced lung tumor incidence and Nectin2/Tigit-associated immunosuppression. ST6GalNAc-I–deficient cells exhibited reduced P-DMEA metabolite levels, while administration of P-DMEA promoted LUAD cell proliferation via MUC5AC. MUC5AC interacted and colocalized with PRRC1 in the Golgi, suggesting a potential role for PRRC1 in MUC5AC glycosylation. Mice injected with ST6GalNAc-I/MUC5AC-deficient cells (human LUAD) exhibited reduced lung tumor incidence, angiogenesis, and liver metastases. Mechanistically, ST6GalNAc-I/MUC5AC regulates VCAN-V1, a key factor in tumor matrix remodeling during angiogenesis and metastasis. These findings demonstrate that ST6GalNAc-I–mediated sialylation of NECTIN2/MUC5AC is critical for immune evasion and tumor angiogenesis. Targeting this pathway may prevent LUAD development and/or metastasis.

Small cell lung cancer (SCLC) is a lethal lung malignancy which is associated with distant metastasis and chemoresistance. Limited targeted therapies further worsen disease outcomes. Single-cell and bulk RNA-sequencing (RNA-seq) datasets were analyzed that revealed FOXM1 as a potential targeting candidate in SCLC. High FOXM1 expression in human and murine SCLC tissues and cell lines was observed. Interestingly, chemoresistant (CR) SCLC cells exhibited substantially higher FOXM1 expression compared to naïve SCLC. Furthermore, FOXM1 inhibition in combination with platinum-based chemotherapy showed synergistic anticancer effects in vitro and in vivo xenograft and spontaneous (RPM: RB1^fl/fl; TP53^fl/fl; LSL-MYCT58A) mouse models of SCLC. Mechanistically, RNA-seq analysis revealed that FOXM1 inhibition altered the Aurora Kinase B (AURKB) signaling pathway. Notably, FOXM1 inhibition enhanced T cell activation, supported differentiation of CD8+ T cells, and T cell-mediated killing of cancer cells. Additionally, FOXM1 inhibition enhanced CD8+ T cell and macrophage recruitment in the TME of immunocompetent RPM model. This study demonstrates that FOXM1 targeting small molecule inhibitors (FOXM1i) has the potential to be a novel therapeutic strategy to combat SCLC progression, including chemotherapeutic resistance and reshaping the anti-tumor immune response.