Frontiers in Immunology | Notable Article Title: Single-cell RNA Sequencing and Proteomics Reveal SIRPα-CD47 Immune Checkpoint and Glycolysis-driven Immune Evasion Mechanism in Cardiac Myxoma

This study combines single-cell sequencing with proteomics analysis to systematically elucidate the microenvironmental cell composition, metabolic profiles, and immune evasion mechanisms of cardiac myxoma (CM) for the first time. It demonstrates that glycolytic pathway activation promotes M2 polarization of tumor-associated macrophages and that the SIRPα-CD47 immune checkpoint inhibits phagocytosis by antigen-presenting cells, providing theoretical foundations for CM immunotherapy.

 

Literature Overview
This article titled 'Single-cell RNA sequencing and proteomics uncover SIRPα-CD47 immune checkpoint and glycolysis-driven immune evasion in cardiac myxoma' published in Frontiers in Immunology reviews single-cell sequencing and proteomics studies on CM, systematically analyzing its tumor microenvironment, cellular origins, and immune evasion mechanisms to provide novel therapeutic insights for this rare cardiac tumor.

Background Knowledge
Cardiac myxoma represents a rare primary cardiac tumor with potential lethality. Surgical resection remains the primary treatment due to the lack of systematic therapeutic strategies. Recent advances in single-cell RNA sequencing (scRNA-seq) and proteomics have enabled comprehensive tumor microenvironment characterization through cellular heterogeneity and signaling pathway analysis. This study pioneers multi-omics integrated analysis in CM, revealing that activated tumor-associated fibroblasts (apCAFs) recruit immune cells via MIF and ANXA1 chemokines, while CM cells exploit the SIRPα-CD47 axis to evade phagocytosis. Notably, glycolytic activation generates metabolic intermediates that induce TAM M2 polarization and IL-10 secretion, establishing immunosuppressive microenvironment. These findings identify novel therapeutic targets for CM immunotherapy and metabolic intervention.

 

 

Research Methods and Experiments
This study employed single-cell RNA sequencing (scRNA-seq) combined with proteomics analysis, integrated with pseudotime trajectory reconstruction, cell-cell communication networks, Western blot validation, and organoid modeling to systematically characterize cellular composition, metabolic signatures, and immune evasion mechanisms in CM microenvironment.

Key Conclusions and Perspectives

• scRNA-seq identified 24 distinct cell subpopulations including cardiomyocytes, endothelial cells, fibroblasts, lymphocytes, myeloid cells, and smooth muscle cells, demonstrating significant cellular composition differences between CM and adjacent tissues
• Pseudotime trajectory analysis traced CM tumor origins to mesenchymal stem cells (MSCs), showing CD34 upregulation alongside ALCAM, CD44, and ICAM1 downregulation
• Glycolysis pathway exhibited hyperactivation in CM, with Western blot confirming elevated glycolytic enzymes (PKM2, PFKP, ENO1), while glycolytic inhibitors effectively suppressed organoid growth
• Activated tumor-associated fibroblasts (apCAFs) recruited immune cells through chemokines MIF and ANXA1 to shape immunosuppressive microenvironment
• Tumor-associated macrophages (TAMs) predominantly displayed M2 polarization, with Western blot validating IL-10 overexpression that suppresses T-cell activation
• Integrated scRNA-seq and ChIP-seq analysis revealed transcription factor REL binding to IL-10 promoter region, mediating glycolytic metabolite-induced M2 polarization

Research Significance and Prospects
This study pioneers the systematic characterization of multi-omics features in cardiac myxoma, unveiling unique immune microenvironment and metabolic reprogramming mechanisms. The findings establish theoretical foundations for targeted therapies against CD47 and IL-10 immune checkpoints. Notably, glycolytic inhibitors demonstrate effective growth suppression of CM organoids, suggesting metabolic intervention as a promising therapeutic strategy. Future research should validate the conservation of these immune checkpoints and metabolic pathways across other cardiac tumors to enable personalized treatment approaches.

 

 

Conclusion
This multi-omics integrated analysis study systematically characterized cardiac myxoma (CM) microenvironment features and immune evasion mechanisms for the first time. The research team employed scRNA-seq, proteomics, pseudotime trajectory analysis, and cell communication networks to demonstrate CM tumor origins from MSCs with glycolysis-driven metabolic reprogramming. apCAFs were shown to secrete chemokines recruiting immune cells, while CM cells evade phagocytosis through SIRPα-CD47 checkpoint engagement. Concurrent glycolysis activation induces TAM M2 polarization and IL-10 secretion, creating immunosuppressive niches. These mechanistic insights provide novel therapeutic strategies for CM targeting and establish fundamental framework for rare cardiac tumor biology research.

 

Xinyuan Zhu, Qingle Gao, Xintong Dai, Hongyan Zhai, and Changliang Shan. Single-cell RNA sequencing and proteomics uncover SIRPα-CD47 immune checkpoint and glycolysis-driven immune evasion in cardiac myxoma. Frontiers in Immunology.