Stem cells at the tumor frontier: Mechanistic insights, therapeutic challenges, and emerging horizons

Stem cell-based approaches are rapidly expanding the therapeutic repertoire against cancer by combining targeted delivery, immune modulation, and cellular engineering. This review synthesizes current knowledge across four interconnected domains: hematopoietic stem cells (HSCs), which serve as mediators of graft-derived antitumor immunity and as platforms for lineage-engineered immune effectors; mesenchymal stromal/stem cells (MSCs), which exhibit tumor-tropic homing and can function as context-dependent modulators or carriers within the tumor microenvironment (TME); induced pluripotent stem cells (iPSCs), which provide a scalable source for generating autologous or allogeneic immune effector cells and designer cell therapies; and cancer stem cells (CSCs), which underlie therapeutic resistance, minimal residual disease, and relapse. We evaluate promising translational strategies including chimeric antigen receptors (CAR)-engineered HSC and iPSC-derived effectors, MSC-mediated targeted delivery of therapeutics, and extracellular vesicles (EVs) engineering alongside critical biological and manufacturing barriers. Principal challenges include the context-dependent pro- versus antitumor activities of MSCs, the tumorigenic risk associated with pluripotent-derived products, immunological compatibility and durability of responses, and product heterogeneity that complicates reproducibility and regulatory assessment. To accelerate safe clinical translation, we recommend standardized functional characterization assays, rigorous in vivo safety and efficacy testing across tumor models, adoption of robust potency and identity metrics, and strategic combinations of molecular engineering with controllable safety switches and immune-modulating adjuncts. By aligning mechanistic insight with translational priorities, the field can prioritize approaches most likely to deliver durable, safe, and broadly applicable cell-based cancer therapies.