?Colorectal cancer treatment has entered the immunotherapy era. While immunotherapy has markedly improved outcomes for microsatellite instability-high (MSI-H) patients, the majority of microsatellite stable (MSS) cases remain unresponsive to immune monotherapy, leading to distinct "cold" and "hot" tumor response states. Transforming "cold tumors" into "hot tumors" is a pivotal research focus. Drug repurposing combined with immunotherapy emerges as a novel strategy that enhances efficacy and reduces adverse effects by repurposing existing drugs, while addressing comorbidities. This approach offers cost-effective and rapid clinical translation. This review systematically explores the potential and challenges of this synergistic approach. In the future, efforts can be focused on initiating prospective studies among the neoadjuvant treatment population, improving drug delivery approaches with the help of materials science, and identifying immune-favorable subgroups. Additionally, considering the characteristics of comorbidity between chronic diseases and colorectal cancer against the backdrop of China's aging society, large-scale multicenter retrospective analyses should be conducted to screen drugs, clarify the interactions between chronic disease medications and immune checkpoint inhibitors (ICIs). This aims to provide more precise combined treatment guidance for colorectal cancer patients, especially those with comorbid chronic diseases, and help achieve the goals of organ preservation and quality of life improvement for more patients.

?Colorectal cancer treatment has entered the immunotherapy era. While immunotherapy has markedly improved outcomes for microsatellite instability-high (MSI-H) patients, the majority of microsatellite stable (MSS) cases remain unresponsive to immune monotherapy, leading to distinct "cold" and "hot" tumor response states. Transforming "cold tumors" into "hot tumors" is a pivotal research focus. Drug repurposing combined with immunotherapy emerges as a novel strategy that enhances efficacy and reduces adverse effects by repurposing existing drugs, while addressing comorbidities. This approach offers cost-effective and rapid clinical translation. This review systematically explores the potential and challenges of this synergistic approach. In the future, efforts can be focused on initiating prospective studies among the neoadjuvant treatment population, improving drug delivery approaches with the help of materials science, and identifying immune-favorable subgroups. Additionally, considering the characteristics of comorbidity between chronic diseases and colorectal cancer against the backdrop of China's aging society, large-scale multicenter retrospective analyses should be conducted to screen drugs, clarify the interactions between chronic disease medications and immune checkpoint inhibitors (ICIs). This aims to provide more precise combined treatment guidance for colorectal cancer patients, especially those with comorbid chronic diseases, and help achieve the goals of organ preservation and quality of life improvement for more patients.