Abstract Cancer stem cells (CSCs) are a small subset of cells that possess unique characteristics, including the ability to initiate and sustain tumor growth, self-renew, and differentiate into various types of cancer cells. They play a crucial role in tumor progression, metastasis, and recurrence. In recent years, CSCs have garnered significant attention due to their involvement in therapeutic resistance to both conventional and novel cancer treatments, including immunotherapy. This review delves into the fundamental properties of CSCs—molecular, cellular, and metabolic—focusing particularly on their immunomodulatory effects. We propose a comprehensive model that reflects the involvement of CSCs in various interlinked contexts, including key signaling pathways, the suppressive microenvironment, and the surrounding stromal components. Through this triaxial conceptualization, we highlight the key role of the stemness-orchestrated architecture in contributing to therapeutic failure. We present evidence gathered from diverse clinical settings, demonstrating a tight correlation between a stem tumor phenotype and poor clinical outcomes, including reduced survival rates and dampened response to immune checkpoint inhibitors (ICB). Finally, we propose therapeutic interventions specifically designed to disrupt the architecture of cancer stemness. These include vaccination against CSC antigens, differentiation therapies, cellular therapies, and combinatorial approaches. In summary, this review apprises an integral, up-to-date perspective that redefines the role of CSCs, positioning them at the core of immunotherapeutic resistance.
Gajón et al. (2026) studied this question.