Inflamed Yet Immune-Evasive? A Transcriptomic Meta-Analysis Identifies Conserved Inflammatory, Developmental, and Neuronal Signatures Associated with Polyploid Giant Cancer Cells
Abstract
Polyploid giant cancer cells (PGCCs) are increasingly recognized as major drivers of therapy resistance and tumor relapse, yet the conserved molecular programs underlying their persistence remain incompletely defined. To identify genes consistently deregulated across eight independent datasets, we performed an integrative transcriptomic analysis of PGCCs derived from prostate, ovarian, and breast cancers. By focusing on consistently up- or down-regulated genes that were expressed in at least five datasets and showed a concordant direction of expression across more than 70% of datasets and met a significance threshold of adjusted p < 0.05, we defined the core regulatory architecture stabilizing the PGCC state under therapeutic stress. Our analysis reveals that PGCCs exhibit a paradoxical ranscriptomic signature consistent with cytolytic activity alongside reduced immune detection. These cells activated pro-inflammatory cytokine and chemokine signaling while simultaneously engaging immune-evasion mechanisms, including PD-L1-associated and virus-like escape programs. Concurrently, PGCCs displayed transcriptional features characteristic of immune-privileged cellular states, including embryonic development, reproductive programs, senescence-associated survival, apoptosis resistance, and deep dormancy marked by coordinated suppression of major housekeeping processes. Notably, PGCCs also activated neuronal differentiation and neurodegeneration-associated pathways, including axon…
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