Immunomodulatory Role of Stem Cells in Cancer: A Landscape of Tumor-Promoting and Tumor-Inhibitory Effects

Stem cell therapy has emerged as a transformative frontier in cancer treatment, harnessing the unique immunomodulatory capabilities of stem cells to reshape anti-tumor immune responses. Mesenchymal stem cells (MSCs), hematopoietic stem cells (HSCs), induced pluripotent stem cells (iPSCs), and cancer stem cells (CSCs) dynamically interact with innate and adaptive immune systems within the tumor microenvironment (TME). MSCs secrete cytokines such as IL-6, TGF-β, and VEGF, which exhibit context-dependent effects on cytotoxic T lymphocytes (CTLs), regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs). These effects vary according to factors such as MSC tissue origin, tumor type, inflammatory status, and the cytokine milieu. MSCs can also modulate tumor-associated macrophage (TAM) polarization, but the direction of polarization toward pro-tumor M2-like or anti-tumor M1-like phenotypes is highly dependent on the surrounding TME. Conversely, CSCs drive immune evasion by expressing checkpoint molecules (e.g., PD-L1) and recruiting immunosuppressive cells, illustrating stem cells’ paradoxical roles in cancer progression. Despite their promise, challenges persist: the TME’s complexity, safety concerns (tumorigenicity, immune rejection), and a lack of standardized protocols impede clinical translation. Innovations such as genetically engineered stem cells for targeted drug delivery, their potential combination with immunotherapies such as CAR-T cells and checkpoint inhibitors, and personalized approaches tailored to tumor-specific profiles offer promising experimental strategies to enhance efficacy. This review underscores stem cells’ potential role in rebalancing immune responses while emphasizing the need for further research to refine their therapeutic application. Although hematopoietic stem cell transplantation is clinically established for selected hematological malignancies, most other stem-cell-based immunomodulatory approaches remain preclinical or are under early clinical investigation.