Immune Editing of Stem Cell Fate: Implications for Cancer Initiation and Therapy Resistance

Abstract

Stem cell fate has traditionally been viewed as a product of intrinsic transcriptional programs and epigenetic regulation operating within specialized tissue niches. However, growing evidence suggests that immune-derived signals constitute a powerful and underappreciated force shaping stem cell behavior across both physiological and pathological contexts. In parallel, the concept of cancer immunoediting has revealed how immune pressure selects for tumor cell variants capable of survival, dormancy, and immune evasion. This review integrates these paradigms to propose immune editing of stem cell fate as a unifying framework linking inflammation, cellular plasticity, and malignant evolution. Recent studies demonstrate that immune-derived cytokines, inflammatory mediators, and checkpoint signaling pathways such as IL-6/STAT3, NF-κB, TGF-β/SMAD, and PI3K/AKT signaling actively reprogram stem and progenitor cells, promoting dedifferentiation, quiescence, epithelial-mesenchymal plasticity, and the persistence of stem-like phenotypes. In normal tissues, immune regulation helps balance regeneration and stem cell exhaustion, whereas under chronic inflammatory conditions and within the tumor microenvironment, immune-mediated selective pressures favor the emergence and maintenance of cancer stem cell-like states. This review further discusses how immune checkpoints such as programmed death-ligand 1 (PD-L1) and CD47 function beyond immune evasion by directly contributing to stemness maintenance and therapy resistance. Advances in single-cell transcriptomics, spatial profiling, and systems-level analyses are increasingly revealing the complex immune-stem cell interactions that shape tumor evolution. Finally, this review examines how chemotherapy and immunotherapy can inadvertently impose immune-selective pressures that enrich resistant stem-like populations, ultimately driving relapse and metastasis. By reframing stem cell fate as an immunologically sculpted and dynamically edited process, this review highlights emerging conceptual and therapeutic opportunities to disrupt immune-stem cell signaling networks and develop more effective strategies for durable cancer control.