Innovative gene engineering strategies to address tumor antigen escape in cell therapy

Tumor antigen escape limits the durability of antigen-specific immunotherapies, particularly chimeric antigen receptor (CAR)-based treatments. Malignant cells evade detection through six routes: antigen mutation or alternative splicing, impaired antigen processing, lineage switching, membrane redistribution, trogocytic epitope masking, and CAR-induced shielding during autologous manufacture. First noted in blood cancers, these tactics increasingly appear in solid tumors, where heterogeneity and immune suppression exacerbate escape. Emerging countermeasures broaden or restore antigen recognition: multi-specific modalities (dual/tandem CARs, bispecific engagers, adaptor CARs), logic-gated synNotch circuits, antigen-upregulating mRNA vaccines and epigenetic drugs, and non-conventional effectors such as invariant natural killer T (iNKT), gamma delta T (γδ T), and mucosal-associated invariant T (MAIT) cells. Collectively, these advances signal a shift toward adaptable, off-the-shelf, biomarker-guided platforms designed to keep pace with tumor evolution and achieve escape-resistant immunity.