iPSC-Derived Polyvalent Vaccines as Ontogenetically Informed Immunogens for Overcoming Immune Refractoriness in Microsatellite-Stable Colorectal Cancer: A New Frontier in Cancer Immunotherapy

Colorectal carcinoma (CRC) exerts a growing global disease burden, with microsatellite-stable/proficient mismatch repair (MSS/pMMR) tumors exhibiting intrinsic refractoriness to immune-checkpoint blockade (ICB) owing to low tumor mutational burden, limited neoantigenicity, and an immunosuppressive tumor microenvironment (TME) dominated by regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). This review evaluates induced pluripotent stem cell (iPSC)–derived polyvalent vaccines as ontogenetically recapitulative immunogens capable of reinstating broad antitumor immunity. Reprogramming induces re-expression of oncofetal tumor-associated antigens, including cancer-testis antigens (NY-ESO-1, MAGE-A3), aberrant glycoforms of CEA and MUC1, and clinically actionable neoepitopes such as KRAS^G12D/V, thereby promoting epitope spreading and immunogenic cell death. Irradiated autologous or syngeneic iPSCs, delivered with Toll-like receptor 9 agonists, facilitate robust MHC I/II cross-presentation, driving CD8⁺ cytotoxic T-cell activation, Th1 polarization, perforin/granzyme-mediated cytolysis, and favorable effector-to-suppressor ratios. Preclinical models of melanoma, pancreatic ductal adenocarcinoma, and MSS CRC demonstrate prophylactic and therapeutic efficacy, with neoantigen-enhanced iPSCs synergizing with radiotherapy-induced DAMPs to achieve durable regressions and memory T-cell formation. Translational priorities include CRISPR-engineered hypoimmunogenic iPSC platforms, GMP-compatible non-integrating reprogramming, and combinatorial integration with STING agonists, ICB, CAR-NK cells, and LNP-mRNA constructs to enable biomarker-guided clinical deployment in minimal-residual-disease CRC.