Colorectal cancer is a leading cause of cancer-related deaths. The traditional therapeutic strategies, such as chemotherapy and surgery, which are generally used to treat colorectal cancer are invasive and often accompanied by significant side effects. Chimeric antigen receptor- T (CAR-T) cell therapy is effective, particularly in treating hematological malignancies; however, the treatment of solid tumors such as colorectal cancer is difficult. These challenges include poor targeting, loss of function, inadequate expansion, and short-lived persistence of CART cells. Some researchers have developed a novel approach to overcome these limitations by using the probiotic bacterium Escherichia coli Nissle 1917 (EcN) and integrating PD-1/CD28 receptors into CAR-T cells. EcN bacteria naturally target the tumor microenvironment (TME) and can be genetically engineered to release synthetic antigens at the tumor site. This improves the targeting ability of CAR-T cells, ensuring that they localize and activate precisely where needed. Additionally, PD-1/CD28 receptor integration enhances the efficacy of CAR-T-cells by converting inhibitory signals into costimulatory signals, thus increasing the activation, proliferation, and persistence of T-cells. This approach has shown promising preclinical results, indicating improved targeting, activation, and longevity of CAR-T cells in solid tumors. Researchers should next focus on optimizing bacterial engineering, enhancing CAR-T-cell design, and conducting rigorous clinical trials to validate the safety and effectiveness of this combined therapy. Their findings may revolutionize treatment for colorectal cancer.