Engineering CAR-T cell therapies for digestive tract cancer: advances, challenges, and strategies to overcome tumor heterogeneity and immunosuppressive barriers.

CAR-T therapy yields remarkable clinical efficacy against hematological malignancies, yet its translation to solid tumors, particularly gastrointestinal cancers, is impeded by multiple bottlenecks including antigen heterogeneity, immunosuppressive tumor microenvironments and metabolic inhibition. This review systematically summarizes coping strategies for these barriers. Claudin-18.2, B7-H3 and c-Met represent attractive therapeutic targets eliciting tumor-specific cytotoxicity in gastric, colorectal and esophageal cancers. Structural modifications such as dual-targeted CARs, cytokine-expressing constructs and logic-gated receptors improve antigen specificity and mitigate off-tumor toxicity. Combination regimens with radiotherapy, immune checkpoint inhibitors and TME-modulating agents synergistically boost CAR-T infiltration, persistence and effector activity. Unresolved hurdles still involve antigen loss, production scalability and inconsistent clinical responses, which may be tackled by γδT-based platforms, synthetic biology and universal CAR designs. Adopting a challenge-solution paradigm, this review integrates cutting-edge clinical data to objectively dissect CAR-T progress in digestive tract malignancies and proposes a systematic optimization roadmap for future translational development.