Cancer stem cells (CSCs), also known as tumor-initiating cells, represent a critical population of tumor cells with self-renewal ability, capacity to differentiate into distinct tumor progeny, and ability to resist therapies [1]. Although their prevalence varies across tumor types, CSCs usually represent a very small subset of tumor cells (usually <0.01–4 %, and up to more than 25 % in advanced melanoma) [2]. Despite their rarity, CSCs are increasingly recognized as primary contributors of tumor heterogeneity, metastasis, immune evasion, therapy resistance and cancer relapse [3], [4].

Importantly, CSCs do not exhibit fixed characteristics but rather possess the capacity to dynamically and reversibly switch between stem-like (CSC) and differentiated (non-CSC) phenotypes. This plasticity enables tumor cells to respond to changing environmental conditions, allowing them to re-acquire stem-like characteristics to maintain the CSC reservoir or, conversely, losing stemness to generate heterogenous tumor cell populations. Those phenotypic changes are typically associated with epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET), which are reversible processes collectively referred to as epithelial-mesenchymal plasticity (EMP). While EMT facilitates intratumor CSC migration and dissemination through blood circulation, MET is particularly relevant to metastatic CSCs to reacquire epithelial traits necessary for secondary tumor formation at distant sites [5], [6]. Concurrently, CSCs can also undergo asymmetric divisions, yielding one stem-like cell and one differentiated tumor cell with strong proliferative ability. The capacity of CSCs to initiate tumors has been validated through transplantation studies demonstrating that even limited numbers of CSCs can produce heterogeneous tumors [6], [7]. Furthermore, in various cancers, CSCs often exploit reversible quiescence (dormancy) to evade cancer therapies that actively target proliferating cells (e.g. chemotherapy), thereby persisting as minimal residual disease and eventually driving relapse, sometimes several years after initial treatment [8], [9]. In accordance with their specific characteristics, CSCs display elevated expression of stemness and survival factors such as SOX2, NANOG and OCT4. Cell surface and intracellular markers such as CD44, CD24, CD133, ALDH1, and CXCR4 (circulating CSCs) are commonly used to identify CSCs across various human cancers [10], [11]. Nevertheless, their relevance and specificity may differ across tumor types which can complexify their detection [11].

Among external signals, interferons (IFNs) have emerged as significant modulators of CSC fate. IFNs are classified into three types: Type I (IFN-α, β, ε, κ, ω), Type II (IFN-γ), and Type III (IFN-λ), with Type I IFN-α/β and Type II being the most studied in the context of cancer immunity [12]. IFN-α/β (IFN-I) are mainly produced by myeloid, epithelial cells and fibroblasts, whereas IFN-γ is predominantly secreted by activated effector cells such as T and NK cells. Although both IFN-I and IFN-γ can have antitumor effects, they may also paradoxically contribute to tumor progression and immune escape when those signals become persistent or co-opted by tumor cells. By shaping CSC survival, plasticity, and immune interactions, IFNs represent a double-edged cytokine axis whose context-dependent effects must be carefully managed for successful therapeutic application.

In this review, we explore how IFNs directly affect tumor cells to regulate their development, modulating CSC plasticity and influencing therapy outcomes. We examine the dual, context-dependent effects of IFNs on CSCs and provide mechanistic insights that may inform the strategic development of IFN-based biomarkers and therapeutic approaches. By understanding conditions that determine whether IFNs may suppress or promote CSCs, we seek to clarify both potential limitations and clinical opportunities, establishing a foundation for optimized therapies and biomarkers that address CSC-mediated resistance.