iPSC-derived polyvalent vaccines as ontogenetically informed immunogens toward overcoming immune refractoriness in microsatellite-stable colorectal cancer: An emerging 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 synthesizes evidence on induced pluripotent stem cell (iPSC)-derived polyvalent vaccines as ontogenetically recapitulative immunogens, evaluating their mechanistic basis, preclinical efficacy across cancer models, and translational prospects in MSS CRC. Reprogramming induces re-expression of oncofetal tumor-associated antigens, including cancer-testis antigens (NY-ESO-1, MAGE-A3) and aberrant glycoforms of CEA and MUC1, that are natively shared between iPSCs and CRC cells. Clinically actionable neoepitopes such as KRAS^G12D/V are not a consequence of reprogramming itself but can be introduced into iPSCs by deliberate genetic engineering (neoantigen-augmented iPSCs), complementing this native oncofetal repertoire and broadening the antigenic payload available for epitope spreading following vaccine-induced tumor cell death.

Irradiated autologous or syngeneic iPSCs, delivered with TLR9 agonists, drive 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.