Emerging cell therapies for gastrointestinal cancers: Advances and future perspectives

Gastrointestinal (GI) cancers, including colorectal and pancreatic cancers, remain among the most lethal cancers worldwide. These tumors often exhibit resistance to immune checkpoint inhibitors, largely due to microsatellite stability and a profoundly immunosuppressive tumor microenvironment (TME). While chimeric antigen receptor (CAR) T cell therapy has demonstrated curative potential in hematological cancers, its translation to solid tumors has been limited by challenges such as antigen heterogeneity, physical barriers to infiltration, and TME-mediated immunosuppression. Gene-editing technologies, including CRISPR-Cas9, have catalyzed the development of next-generation cellular immunotherapies. By precisely modifying T cells, natural killer (NK) cells, and mesenchymal stem/stromal cells (MSCs), it is possible to enhance their functionality, persistence, and safety. This review highlights the clinical progress of gene-edited cell therapies and specifically explores the synergistic "one-two punch" potential of engineered MSCs as TME remodeling platforms. By acting as localized delivery vehicles for cytokines or prodrug-activating enzymes, MSCs can modulate TME, thereby facilitating the infiltration and sustained cytotoxic activity of CAR T or CAR NK cells. Finally, we address critical translational challenges and propose future directions that integrate multi-omics to identify novel therapeutic agents for cellular immunotherapy in GI oncology.