Translational potential of trained immunity in cancer

Abstract The term trained immunity (TRIM) was coined to describe a form of innate immune memory, whereby prior stimulation induces durable rewiring, mainly at the epigenetic level, in innate immune cells and their bone marrow precursors. In cancer, this concept has gained increasing relevance, as innate immune cells and myelopoiesis crucially modulate anti-tumor immune responses and immunotherapy outcome. TRIM can act at the level of mature myeloid cells, but also in hematopoietic stem and progenitor cells, thereby altering myeloid cell function over prolonged periods. In this context, microbial and fungal-derived TRIM agonists, including Bacillus Calmette-Guérin and β-glucan, can boost anti-tumor immunity by generating monocytes, macrophages, neutrophils and dendritic cells with enhanced anti-tumor actions. These trained innate immune cells can promote tumor cell killing, antigen presentation, T cell activation and improve responses to immune checkpoint blockade. In this review, we discuss the role of TRIM in cancer and highlight emerging translational strategies that exploit innate immune memory to enhance anti-tumor immunity.