Immunosenescence in digestive system cancers: Mechanisms, research advances, and therapeutic strategies

Increasing lifespans and external environmental factors have contributed to the increase of age-related diseases, particularly cancer. A decrease in immune surveillance and clearance of cancer cells is the result of immunosenescence, which involves the remodeling of immune organs, the changes and functional decline of immune cell subsets, in association with systemic low-grade chronic inflammation. Stem cells aging in bone marrow and thymic involution are the most important causes of immunosenescence. Senescent cancer cells promote the differentiation, recruitment, and functional upregulation of immune-suppressive cell subsets e.g. regulatory T cells (Tregs), myeloid-derived suppressor cell (MDSC), tumor-associated macrophages (TAMS) through senescence-associated secretory phenotype (SASP) further exacerbating the immunosuppressive microenvironment. For digestive system cancers, age-related damage to the intestinal mucosal barrier, the aging of gut-associated lymphoid tissue (GALT), exposure to xenobiotic stimuli throughout life, and dysbiosis make the local immune microenvironment more vulnerable. This article systematically reviews the research progress of immunosenescence and immune microenvironment in digestive system cancers, as well as the exploration of related therapy strategies, hoping to point out new directions for research in the digestive system cancers.