The review emphasizes that iPSCs can be directionally differentiated into a wide array of functional immune effector cells, including T cells, natural killer cells, and macrophages, each of which has shown strong anti-tumor activity in preclinical studies. Among these, iPSC-derived T cells engineered with chimeric antigen receptors, or CARs, have demonstrated superior expansion, persistence, and cytotoxicity compared with traditional autologous CAR-T cells. By reprogramming antigen-specific T cells into T cell-derived iPSCs, researchers can preserve the original T cell receptor information and then redifferentiate the cells into large, homogeneous populations with the same tumor-targeting specificity. CRISPR editing targeting the RAG1 and RAG2 recombinase genes in these T-iPSCs blocks endogenous random TCR rearrangement, producing antigen-specific CD8αβ T cells with a single stable T cell receptor and significantly improving TCR repertoire homogeneity.

Further refinements have pushed the platform toward clinical translation. Researchers have developed trimodal iPSC-T cells that simultaneously express a CAR, a T cell receptor, and humanized CD16, designed to overcome tumor heterogeneity through synergistic antibody-dependent cell-mediated cytotoxicity. Other teams have optimized proliferation and persistency by screening IL-15 and IL-15 receptor alpha co-expressing clones, enabling engineered human iPSC-derived CAR T cells to exhibit therapeutic efficacy across multiple tumor-bearing animal models. The review notes that iPSC-derived T cell products have progressed from basic proof-of-principle experiments into preliminary clinical trials, with FT819, an iPSC-derived CD19 CAR-T therapy in which the CAR is knocked into the TRAC locus while the endogenous T cell receptor is ablated, showing promising tumor-killing efficacy against B-cell malignancies and effective B-cell depletion in patients with systemic lupus erythematosus in a phase I trial without dose-limiting toxicities, immune effector cell-associated neurotoxicity syndrome, or graft-versus-host disease.

iPSC-derived natural killer cells have attracted considerable attention for their mature phenotype, strong cytotoxicity, and scalability. Unlike peripheral blood or umbilical cord blood sources, which are limited by donor scarcity and expansion bottlenecks, iPSCs can be differentiated into NK cells through feeder-free systems, and the resulting cells from a clonal starting population are highly homogeneous, overcoming donor variability. Gene editing can further enhance their function: CD226-overexpressing iPSC-NK cells showed enhanced anti-acute myeloid leukemia activity, increased cytokine release at low effector-to-target ratios, and upregulated cytotoxicity pathways, while NKG2A knockout significantly enhanced killing ability against tumors and viral infections. CALHM2-knockout CAR NK cells exhibit stronger in vivo antitumor effects and overcome resistance mechanisms. The review highlights that this preclinical progress was quickly followed by clinical transition, with a landmark first-in-human trial evaluating iPSC-derived CD19-directed CAR-NK cells in patients with relapsed or refractory B-cell lymphoma demonstrating that these cells can be safely used in the clinic across 86 patients, with cytokine release syndrome occurring in only 6 to 13 percent of patients at maximum grade 2 and deep, durable responses observed in both indolent and aggressive lymphomas.

iPSC-derived macrophages, or iMacs, offer a distinct strategy for solid tumor immunotherapy based on phagocytosis and cytokine secretion. Macrophages constitute the largest immune cell population in the solid tumor microenvironment, and their phenotypes are highly heterogeneous, with subgroups playing antagonistic roles in tumor progression. CAR-engineered iMacs targeting prostate stem cell antigen significantly amplify anti-tumor lethality through antibody-dependent cell-mediated cytotoxicity and coordinated pro-inflammatory cytokine release. Second-generation CAR-iMac cells expressing a CD3ζ–TIR signaling domain for orthogonal phagocytosis and antigen-dependent M1 polarization showed significantly improved anti-tumor efficacy against solid tumors. Allogeneic CAR-iMacs co-engineered with membrane-bound interleukin 15 and a truncated epidermal growth factor receptor suicide switch have demonstrated potent antitumor activity against pancreatic cancer and can be cryopreserved as an off-the-shelf product, though their evaluation remains confined to preclinical models with no clinical trials conducted as yet.

Beyond immune cell therapies, the review details how iPSCs can be engineered into tumor vaccines that activate systemic anti-tumor immunity. iPSCs share transcriptomic characteristics and tumor-associated antigens with cancer cells, positioning them as a promising platform for broad-spectrum cancer vaccines. When combined with CpG adjuvant, iPSC-based vaccines simultaneously stimulate cytotoxic antitumor CD8+ T cell effector and memory responses and induce cancer-specific humoral immune responses while relieving immunosuppression by reducing regulatory CD4+ T cells. These vaccines have prevented tumor formation in multiple murine models. Neoantigen-engineered autologous iPSC vaccines showed stronger cytotoxicity and effectively eliminated cancer cells in mouse models of triple-negative breast cancer, and combined with radiotherapy, this approach reduces distant metastasis risk. iPSC membranes, rich in tumor-associated antigens highly expressed in cancer cells but low in normal tissues, can encapsulate adjuvant nanoparticles to form vaccines that stimulate broad-spectrum anti-tumor immunity across five mouse tumor models. iPSC-derived exosome vaccines circumvent the tumorigenic risk while retaining a broad repertoire of stem cell-associated antigens, offering superior cost-effectiveness and therapeutic efficacy compared with other exosome vaccine platforms.

The review also explores a complementary modeling approach in which normal iPSCs can be converted into cancer stem cell-like cells through tumor microenvironmental cues or genetic manipulation. Cancer stem cells possess dual self-renewal and differentiation potential, forming hierarchical tumor structures that drive tumorigenesis, progression, metastasis, and resistance. Mouse iPSCs can be transformed into cancer stem cells in vivo upon co-transplantation with pancreatic cancer cells, and secretory components of the tumor microenvironment are key for this conversion. Tumor-derived extracellular vesicles drive iPSC-to-CSC conversion by delivering specific molecular cargo, while introducing oncogenes or knocking out tumor suppressors in iPSCs increases microenvironment sensitivity. In glioma modeling, inducible endogenous H3.3-K27M mutation enhances proliferative capacity and stemness in iPSC-derived neural stem cells, leading to glioma-like cell formation by disrupting PRC2 complex function and enhancer activity. KRAS p.G12V-mutant iPSCs exhibit constitutive RAS-MAPK pathway activation that drives proliferation, metabolic reprogramming, and malignant transformation, verifying the reliability of the iPSC-CSC transformation model.

Exposure to cancer cell-conditioned medium has become one of the most efficient and reproducible modeling methods in cancer stem cell research. Mouse iPSCs treated with breast cancer cell-conditioned medium maintained tumorigenicity upon serial transplantation in nude mice and retained core CSC characteristics. Human iPSCs exposed to hepatocellular carcinoma Huh7-conditioned medium generated liver cancer stem cells within four weeks without genetic manipulation, and after orthotopic transplantation into the liver, 100 percent of these cells formed highly proliferative and invasive malignant tumors while maintaining tumorigenicity for three consecutive generations. RNA sequencing revealed that tumor microenvironment-driven CSC self-renewal and metastasis proceed through phosphatidylinositol 3-kinase-protein kinase B, vascular endothelial growth factor, and epithelial-mesenchymal transition pathways. Mouse iPSCs cultured in Lewis lung carcinoma-conditioned medium combined with signaling inhibitors could be efficiently converted to cancer stem cells within one week, with the resulting cells showing enhanced tumorigenicity through PI3K-AKT pathway activation and ERK1/2 inhibition.

In the reverse direction, cancer cells can be reprogrammed into cancer-derived iPSCs, resetting them to a pluripotent state while retaining their tumorigenic memory. Since 2010, accumulating evidence has demonstrated that cancer cells, with their inherent self-renewal capacity, telomerase activity, and epigenetic plasticity, can bypass certain reprogramming barriers and even reverse malignant phenotypes upon the introduction of exogenous reprogramming factors. Researchers have successfully generated iPSCs from a variety of human cancer cell lines, including malignant tumors of the blood, digestive system tumors, and other solid tumors. Primary tumor samples offer higher clinical relevance because they preserve the genetic mutation spectrum, chromosomal abnormalities, and heterogeneity of the original tumor to the greatest extent, making models based on them ideal for personalized drug screening and biomarker research. Non-integrating delivery methods such as Sendai virus and episomal plasmids are preferred for cancer-iPSC research to ensure that genetic variation in the generated model originates entirely from the original cancer cells rather than from the reprogramming technology itself.

The review concludes by frankly acknowledging the challenges facing clinical translation of iPSC-guided therapies. Tumorigenicity remains the most fundamental safety concern, as reprogramming factors and residual undifferentiated iPSCs carry carcinogenic potential, and even unexpected proliferative off-target cells have been detected after transplantation of iPSC-derived products in preclinical models. Immunogenicity is more complex than initially anticipated, with abnormal gene expression and residual pluripotent cells eliciting unexpected immune responses even in syngeneic settings. Most iPSC-T cell therapies remain in phase I dose-escalation trials, iPSC-derived tumor vaccines have not yet entered any registered clinical trial, and iPSC-Macs are still awaiting first-in-human validation. The authors recommend developing general-purpose HLA-engineered products or hypoimmunogenic designs to reduce matching needs, introducing neoantigen engineering strategies into iPSC vaccine technology, using nanotechnology to overcome delivery obstacles, and developing fully chemical small-molecule reprogramming methods to avoid gene insertion. Single-cell RNA sequencing and three-dimensional culture systems based on iPSCs can better simulate the in vivo tumor microenvironment, replicating immune cell infiltration and the immunosuppressive microenvironment more realistically than traditional two-dimensional cultures, positioning the iPSC platform to advance precision oncology and personalized cancer treatment in the years ahead.

Subject of Research: Applications of induced pluripotent stem cells in cancer immunotherapy, tumor vaccines, and cancer stem cell modeling

Article Title: Progress in research on the use of induced pluripotent stem cells in tumor prevention, therapy, and tumor modeling

Article References: Liang, S., Zhao, H., Zuo, N., Zhang, B., Chen, M., Zhang, X., Zhang, H., Iqbal, M. O., Wang, Q., & Dong, D. (2026). Progress in research on the use of induced pluripotent stem cells in tumor prevention, therapy, and tumor modeling. Frontiers in Cell and Developmental Biology, 14, Article 1968508. https://doi.org/10.3389/fcell.2026.1968508

Image Credits: AI Generated

DOI: 10.3389/fcell.2026.1968508

Keywords: induced pluripotent stem cells, cancer immunotherapy, CAR-T cells, natural killer cells, tumor vaccines, cancer stem cells, tumor modeling, CRISPR gene editing, tumor microenvironment, precision oncology, cell therapy, reprogramming