# Cancer stem cells and post-therapy tumour recurrence: a systematic review of mechanistic pathways and translational gaps

## TL;DR

This review explores how cancer stem cells contribute to tumor recurrence after treatment and highlights gaps in translating this knowledge into clinical practice.

## Contribution

The paper systematically synthesizes mechanistic pathways linking cancer stem cells to post-therapy recurrence across multiple tumor types.

## Key findings

- Cancer stem cells are associated with treatment resistance and tumor recurrence through chromatin remodeling and metabolic adaptations.
- Key pathways include immune evasion via PD-L1 and transcriptional regulators like MYC and SRY-box transcription factor 2.
- Most studies are preclinical, with limited patient validation and high variability in CSC definitions.

## Abstract

Cancer stem cells (CSCs) are increasingly recognised as pivotal drivers of tumour recurrence and treatment resistance across multiple malignancies. Despite extensive preclinical investigations, the mechanisms by which CSCs mediate relapse after therapy remain insufficiently integrated and poorly translated into clinical frameworks.

This systematic review aimed to synthesise current mechanistic evidence linking CSC biology to post-therapeutic recurrence in solid and hematologic tumours, highlighting recurrent molecular pathways, experimental models and translational gaps.

Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, five major databases (PubMed, Scopus, Web of Science, Embase and ResearchRabbit) were searched without time or language restriction. Eligible studies included original experimental articles investigating the mechanistic role of CSCs in tumour recurrence, therapy resistance or metastatic relapse. A total of 23 studies were included after rigorous screening and data extraction. Risk of bias was assessed using predefined methodological criteria. No meta-analysis was conducted due to mechanistic and qualitative heterogeneity.

Included studies spanned diverse tumour types, including glioblastoma, breast, pancreatic, hepatocellular, colorectal, lung, thyroid and hematologic cancers. CSC-related recurrence was linked to key mechanistic axes: chromatin remodeling (e.g., suppressor of variegation 3-9 Homolog 1, methyltransferase like 16), transcriptional regulators (e.g., SRY-box transcription factor 2, MYC and Transcription factor activating enhancer-binding protein 4), epithelial-to-mesenchymal transition-associated plasticity, immune evasion (Programmed death-ligand 1, stimulator of interferon genes pathway suppression), metabolic rewiring (P-element induced WImpy Testis-like 2–PDK1, ribosomal biosynthesis) and microenvironmental crosstalk (cancer-associated fibroblasts- and myeloid-derived suppressor cells-mediated niches). Across studies, CSCs demonstrated higher resistance to chemotherapy, prolonged survival under treatment stress and robust capacity for tumour regeneration.

The majority of studies were preclinical and varied in CSC definitions and recurrence models. Few incorporated longitudinal tracking or patient-level validation. Overall risk of bias was moderate due to lack of blinding, protocol registration or replication.

CSC-driven recurrence is a multifaceted and dynamic process shaped by epigenetic, transcriptional, metabolic and immunologic adaptations. Single-target strategies are unlikely to achieve durable eradication. Future research must prioritise multi-targeted approaches, integrate CSC endpoints into clinical trials and develop predictive biomarkers of CSC burden. Addressing CSC-mediated relapse is essential for advancing precision oncology and achieving lasting therapeutic responses.