Cell-Based Therapies in GI Cancers: Current Landscape and Future Directions

Cell-based therapies have become integral to the routine clinical management of hematologic malignancies. Tumor-infiltrating lymphocyte (TIL) therapy has demonstrated efficacy in immunogenic solid tumors, such as melanoma. However, in the GI field, evidence supporting the clinical success of cell-based therapies is still awaited. CLDN18.2, a key tight junction molecule in stomach epithelium, has emerged as a promising target for gastric cancer (GC) treatment. Because of its lineage-specific expression, significant efforts have been made to develop chimeric antigen receptor T-cell (CAR-T) therapies targeting CLDN18.2. These therapies have shown encouraging tumor shrinkage in patients with heavily pretreated GC. However, durable responses remain uncommon. CAR-T exhaustion driven by immune-suppressive cells in the tumor microenvironment, along with the heterogeneous expression of target molecules, poses significant challenges. In addition, managing on-target, off-tumor toxicities remains a critical issue in therapies targeting tissue-associated antigens. Next-generation CARs are expected to address these resistance mechanisms. Furthermore, adoptive macrophage and natural killer cell therapies hold promise for not only their efficacy but also for the ease off-the-shelf production. Advanced neoantigen prediction and identification of optimal T-cell activation targets could facilitate the clinical application of TIL and T-cell receptor-T therapies in GI cancers. Cell-based therapies might have the potential to transform the treatment landscape for GI cancers.