Trained Immunity in Cancer: Pathways, Strategies and Emerging Therapies

Cancer immunotherapy has revolutionized oncological treatment; yet, its efficacy is compromised by the immunosuppressive Tumor Microenvironment (TME) and limited T-cell responses. Trained immunity, a newly recognized feature of the innate immune system characterized by memory-like functional reprogramming, offers a viable supplementary approach to enhance immune responses against cancers. Unlike adaptive immunity, which relies on specific antigen recognition, trained immunity augments the readiness of innate immune cells via epigenetic and metabolic reprogramming, facilitating more vigorous responses to subsequent stimuli. Innate immune cells, including as monocytes, macrophages, and natural killer (NK) cells, are essential to this phenomenon. Their enhanced functional state, achieved through exposure to microbial ligands or immunomodulatory agents such as BCG or β-glucans, results in increased cytokine production, elevated phagocytic activity, and greater cytotoxicity in subsequent encounters with infections or tumor antigens. These trained responses are transient but can be maintained through the reprogramming of Hematopoietic Stem and Progenitor Cells (HSPCs), hence promoting long-term enhancement of innate immunity. This review comprehensively analyzes the molecular and cellular mechanisms behind trained immunity, including its induction via histone modifications, DNA methylation, and shifts in cellular metabolism. We examine the therapeutic relevance of trained immunity in cancer treatment, particularly its role in enhancing the efficacy of existing medicines, such as immune checkpoint inhibitors and cancer vaccines. We highlight novel approaches employing nanoparticles for the direct delivery of therapeutics that stimulate trained immunity within the tumor microenvironment, thereby improving treatment efficacy and minimizing systemic toxicity. Integrating trained immunity into cancer immunotherapy frameworks is a viable strategy to tackle critical challenges such as immune evasion, antigen heterogeneity, and resistance to conventional medicines. Trained immunity can alter the innate immunological environment, potentially promoting a more robust, sustained, and personalized anti-tumor immune response.