Inflamed Yet Immune-Evasive? A Transcriptomic Meta-Analysis Identifies Conserved Inflammatory, Developmental, and Neuronal Signatures Associated with Polyploid Giant Cancer Cells.

Overview

1. Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg 194064, Russia
2. Center of Genetic Reprogramming and Gene Therapy, Institute of Cytology RAS, Saint-Petersburg 194064, Russia

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 guidance, neurogenesis, and calcium signaling. This neuron-like, calcium-dependent stress adaptation program may further enhance immune privilege and long-term survival capacity. We propose that PGCCs represent an immune-adaptive polyploid survival state in which inflammatory and ontogenetic pathways are repurposed to support immune evasion and tumor persistence. By identifying actionable vulnerabilities within calcium signaling, neuronal mimicry, and checkpoint-associated pathways, this study provides a framework for therapeutic strategies aimed at dismantling the PGCC reservoir and preventing tumor relapse.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE195919, at NCBI GEO; found in the text, “4.1. Datasets”

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Materials. Further inquiries can be directed to the corresponding authors.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 2 authors, 10 keywords, 9 MeSH terms, 1 funder, 142 references.

Cite

This paper

Anatskaya, O. V., & Vinogradov, A. E. (2026). Inflamed Yet Immune-Evasive? A Transcriptomic Meta-Analysis Identifies Conserved Inflammatory, Developmental, and Neuronal Signatures Associated with Polyploid Giant Cancer Cells. International journal of molecular sciences, 27(15), 6671. https://doi.org/10.3390/ijms27156671

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