Cuproptosis correlates with immunosuppressive tumor microenvironment based on pan-cancer multiomics and single-cell sequencing analysis

Abstract

Recent studies suggest that cuproptosis, a novel mode of cell death, may be associated with the development of cancer. However, no studies are showing its role in tumorigenesis, progression, and prognosis. In the present study, we comprehensively analyzed the expression difference, gene variation and methylation modification of cuproptosis-related genes (CRGs) in pan-cancer. Then, Single sample gene set enrichment analysis (ssGSEA) was used to calculate individual cuproptosis scores (CS). The association of CS with copy number variation, clinical features, immune-related genes, TMB, MSI, and tumor immune dysfunction and exclusion (TIDE) was comprehensively assessed. Single-cell transcriptome sequencing (scRNA-seq) to analyze the activation of cuproptosis in the tumor microenvironment. Immunohistochemistry (IHC) were used to validate the expression of cuproptosis hub-gene. Our study shows that CRGs were significantly expressed in a variety of tumors, and CDKN2A had the highest mutation frequency (49%) in all tumors. A significant increase in the CS was observed in most cancers and were associated with poor prognosis in the majority of tumors. CS was significantly negatively correlated with tumor microenvironment scores in more than 10 tumors and positively correlated with PD-L1 in 11 tumors, suggesting involvement in tumor immune escape. scRNA-seq suggests that CRG scores significantly increased in the cancer cells. This study opens avenues for further research on the role of cuproptosis in the occurrence and development of cancer and the development of targeted therapies based on cuproptosis.

Copper homeostasis and cuproptosis in cancer immunity and therapy

“…63 Among all cuproptosisrelated genes, CDKN2A has the highest mutation frequency (~49%) in pan-cancer. 64 Experimentally, CDKN2A facilitates proliferative and migrative capacities as well as attenuates cuproptosis of HCC cells. 65 CDKN2A is a target of plicamycin that attenuates cancer progression.…”

Pancreatic cancer environment: from patient-derived models to single-cell omics

“…Given the limited responsiveness of PDAC to current immunotherapeutic strategies involving immune checkpoint blockade or chimeric antigen receptor T-cell therapy, a more comprehensive understanding of the immune microenvironment in PDAC is urgently warranted. 57 The combination of scRNA-seq and spatial transcriptomics reveals the presence of unique immune subsets that may have been previously disregarded in the context of PDAC, as these subsets diverged from immune populations found in neighboring normal regions. 58 The utilization of scRNA-seq analysis has provided insights into the crucial role of neutrophils in innate immunity, as they actively contribute to tumor progression by participating in various processes such as cell proliferation, angiogenesis, tissue remodeling, immunosuppression, and metastasis.…”

Enzyme Core Spherical Nucleic Acid That Enables Enhanced Cuproptosis and Antitumor Immune Response through Alleviating Tumor Hypoxia

“…As our understanding of cuproptosis deepens, its intricate relationship with immune responses becomes more apparent. Cuproptosis plays a pivotal role in the regulation of several immune-related pathways, including inflammation, complement activation, the IL-6/JAK/STAT3 pathway, and interferon-gamma signaling in most tumor types. − However, within the tumor microenvironment, hypoxia, a dominant feature, exerts its influence by promoting local immune suppression. For example, increased expression of hypoxia-inducible factor-1 (HIF-1) in response to hypoxia can affect the activity of pro-inflammatory immune cells, induce immune cells to switch to an immunosuppressive phenotype, and inhibit the activity of effector T cells. − Thus, relieving tumor hypoxia is a promising strategy to enhance tumor immunotherapy.…”