(1) Abstract: 

This review proposes an "athero-oncology" framework to explore selected tumor-like cellular programs in vascular smooth muscle cells (VSMCs) during atherosclerosis, including clonal expansion, phenotypic plasticity, and metabolic adaptation, and discusses pathway-level therapeutic opportunities and boundaries.

(2) Background: 

Atherosclerosis is the primary pathological basis of cardiovascular diseases. The traditional view held that VSMCs are merely passive structural components, but single-cell sequencing and lineage tracing have revealed remarkable plasticity, including clonal expansion and phenotypic switching. This discovery prompted re-examination of VSMC roles in AS from a tumor biology perspective, while fundamental differences between AS and cancer must be clarified.

(3) Main Content: 

The review addresses VSMC tumor-like behaviors, including proliferative expansion and apoptosis resistance, phenotypic plasticity (synthetic, foam cell-like, inflammatory, macrophage-like, fibroblast-like, senescent phenotypes), metabolic reprogramming (glycolysis, glutamine metabolism), epigenetic regulation (DNA methylation, histone modification, RNA methylation), genomic instability, senescence and SASP, immune escape, and pathological angiogenesis. Shared molecular pathways between AS and cancer are also discussed, such as NF-κB, IL-6/STAT3, and PI3K-AKT-mTOR.

(4) Study Design: 

This is a review study. The authors integrate single-cell RNA sequencing, lineage tracing, spatial transcriptomics, epigenetics, and molecular biology evidence, using athero-oncology as a pathway-level heuristic framework to systematically organize VSMC tumor-like behaviors and mechanisms, emphasizing fundamental differences between AS and malignant disease in growth limitation, mutational burden, metastatic potential, and clinical behavior.

(5) Results: 

VSMCs in AS lesions exhibit clonal expansion, functional heterogeneity, and phenotypic plasticity, sharing pathway-level similarities with tumor cells in proliferation, metabolism, epigenetics, and immune microenvironment regulation. Key regulators include KLF4, STAT3, YAP/TEAD, SRF-MYOCD, HIF-1α, and mTOR. Epigenetic modifications such as lactylation, m6A methylation, and histone modification participate in VSMC phenotypic switching. Genomic instability manifests as DNA damage accumulation, telomere dysfunction, and mitochondrial DNA stress. Therapeutic strategies include targeting mTOR, PI3K-AKT, TTK, GLS1, BRD4, and inflammatory pathways, with attention to cell-type specificity and long-term safety.

(6) Future Directions: 

Future studies should use spatial transcriptomics to dynamically track spatiotemporal evolution of VSMC subsets, screen key driver genes conferring clonal advantages, and distinguish harmful VSMC states from protective phenotypes supporting fibrous cap formation and vascular repair. Repurposing anticancer drugs requires pathway-level analogy rather than disease equivalence, with emphasis on cell-type specificity and long-term safety.

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