Exploring the role of metabolic disorders and gut microbiome in immune checkpoint regulation in cancer: PI3K/AKT/mTOR focus.

Metabolic disorders including obesity, hyperglycemia, and dyslipidemia contribute to cancer progression by overactivating signaling pathways, particularly PI3K/AKT/mTOR, thereby promoting tumor cell growth, survival, and migration. These metabolic disruptions also contribute to chronic inflammation, which leads to increased expression of immune checkpoint inhibitory proteins such as PD-L1 on immune and cancer cells, thereby suppressing the function of cytotoxic T cells within the tumor microenvironment. In parallel, gut microbiome dysbiosis characterized by a reduction in SCFA-producing bacteria and an increase in endotoxin-producing microbes results in increased intestinal epithelial permeability, allowing translocation of endotoxins into the bloodstream and activation of APCs. This process shifts the immune balance toward immunosuppressive cell populations and enhances the expression of inhibitory molecules such as PD-L1. This review focuses on the interplay of these factors and investigates the role of the gut microbiome in modulating the efficacy of immunotherapy, highlighting the impact of specific bacterial species in either enhancing or impairing the response to immune checkpoint inhibitors.