Diabetes mellitus (DM) significantly increases the risk for cancer and cancer progression. Hyperglycemia is the defining characteristic of DM and tightly correlates with a poor prognosis in patients with cancer. The hexosamine biosynthetic pathway (HBP) is emerging as a pivotal cascade linking high glucose, tumor progression, and impaired immune function. Here we show that enhanced glucose flow through the HBP drives cancer progression and immune evasion by increasing O-GlcNAcylation in tumor-associated macrophages (TAM). Increased O-GlcNAc skewed macrophage polarization to a M2-like phenotype supporting tumor progression. Finally, we found an upregulation of M2 markers on TAMs in DM2 patients with colorectal cancer compared with nondiabetic normoglycemic patients. Our results provide evidence for a new and targetable mechanism of cancer immune evasion in patients with hyperglycemia, advocating for strict control of hyperglycemia in patients with cancer.

Glioblastoma (GB) is the most aggressive primary malignant brain tumor and is associated with short survival. O-GlcNAcylation is an intracellular glycosylation that regulates protein function, enzymatic activity, protein stability, and subcellular localization. Aberrant O-GlcNAcylation is related to the tumorigenesis of different tumors, and mounting evidence supports O-GlcNAc transferase (OGT) as a potential therapeutic target. Here, we used two human GB cell lines alongside primary human astrocytes as a non-tumoral control to investigate the role of O-GlcNAcylation in cell proliferation, cell cycle, autophagy, and cell death. We observed that hyper O-GlcNAcylation promoted increased cellular proliferation, independent of alterations in the cell cycle, through the activation of autophagy. On the other hand, hypo O-GlcNAcylation inhibited autophagy, promoted cell death by apoptosis, and reduced cell proliferation. In addition, the decrease in O-GlcNAcylation sensitized GB cells to the chemotherapeutic temozolomide (TMZ) without affecting human astrocytes. Combined, these results indicated a role for O-GlcNAcylation in governing cell proliferation, autophagy, cell death, and TMZ response, thereby indicating possible therapeutic implications for treating GB. These findings pave the way for further research and the development of novel treatment approaches which may contribute to improved outcomes and increased survival rates for patients facing this challenging disease.

The evolutionary loss of cytidine monophosphate–N-acetylneuraminic acid hydroxylase (CMAH) abolished endogenous N-glycolylneuraminic acid (Neu5Gc) synthesis in humans, reshaping the sialic acid at the cell surface glycans and influencing immune and metabolic processes. However, whether a human-like sialome modulates the impact of metabolic stress on colorectal cancer (CRC) progression remains unclear. Here, we investigated the diabetes–sialome–tumor axis using a spontaneous CRC model combining conditional Apc mutation with Cmah deficiency, thereby recapitulating the human sialic acid repertoire. Under euglycemic conditions, CPC- Apc Cmah ^-/- mice exhibited reduced polyp numbers and tumor burden compared with WT mice, accompanied by remodeling of the tumor immune microenvironment, including increased tumor-infiltrating leukocytes, enrichment of B cells, and reduced PD-1 expression in B cells and cytotoxic CD8 ⁺ T cells. Induction of chronic hyperglycemia with low-dose streptozotocin revealed a striking genotype-specific effect. Despite comparable hyperglycemia between genotypes, tumor progression was dramatically exacerbated exclusively in Cmah ^-/- mice, with increased tumor burden, accelerated lesion development, and progression toward high-grade dysplasia. Histopathological analyses further revealed increased mesenchymal expansion and close resemblance to colorectal tumors from diabetic patients. Together, these findings demonstrate that a human-like sialome increases susceptibility to metabolic stress and identify CPC- Apc Cmah ^-/- mice as a translationally relevant model for investigating diabetes-associated colorectal carcinogenesis. Graphical Highlights: CMAH loss reshapes the sialome and suppresses spontaneous colorectal tumorigenesis; Neu5Ac-dominant glycocalyx modifies tumor-infiltrating immune cell populations; Hyperglycemia selectively exacerbates tumor progression in Cmah ^-/- mice; Diabetic Cmah ^-/- tumors shift toward high-grade dysplasia with mesenchymal expansion; Cmah ^-/- CPC- Apc model faithfully recapitulates diabetes-associated CRC progression in humans; Loss of CMAH increases susceptibility to hyperglycemia-driven colorectal cancer progression.