iPSC衍生多价疫苗作为发育重演性免疫原克服微卫星稳定结直肠癌免疫难治：癌症免疫治疗的新兴前沿

BACKGROUND: 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).

SCOPE: 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.

KEY FINDINGS: 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.

CONCLUSIONS: 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.