Exploring the landscape of drug resistance in gastrointestinal cancer immunotherapy: A review

Gastrointestinal (GI) cancers pose a significant challenge due to high prevalence and mortality. While advancements in detection and conventional treatments have been made, prognosis often remains poor, particularly for advanced-stage cancers. Immunotherapy has emerged as a transformative approach, leveraging the body immune system against cancer, including immune checkpoint inhibitors (ICIs), cancer vaccines, and adoptive cell transfer. These modalities have shown promise, achieving sustained responses and improved survival in some patients. However, their efficacy in GI cancers is less pronounced, hindered by drug resistance mechanisms that are either intrinsic or acquired over time. This review examines the latest understanding of immunotherapy in GI cancers, focusing on ICIs, cancer vaccines, and adoptive cell transfer, along with their associated outcomes and limitations. It delves into the mechanisms behind drug resistance, including alterations in immune checkpoints, the immunosuppressive tumor microenvironment, and genetic/epigenetic changes. The role of the gut microbiome is also considered as an emerging factor in resistance. To combat drug resistance, strategies such as enhancing immune response, targeting the tumor microenvironment, and modulating resistance mechanisms are explored. The review underscores the potential of ferroptosis induction as a novel approach. Looking forward, it highlights the need for personalized immunotherapies, understanding the influence of the gut microbiome, and further exploration of ferroptosis in overcoming resistance. While challenges persist, the continuous evolution in GI cancer immunotherapy research promises innovative treatments that could significantly improve patient outcomes.