Nanomedicine-enabled reprogramming of macrophage trained immunity to modulate cancer stem cells fate

Tumor-associated macrophages (TAMs) are key regulators of tumor progression and treatment resistance. Among their functions, efferocytosis, the clearance of apoptotic cells, often suppresses antitumor immunity and can support cancer stem cell (CSC) survival in tumors. Trained immunity further shapes this process by reprogramming macrophages through epigenetic and metabolic mechanisms, thereby influencing efferocytic activity and CSC-related phenotypes. These findings identify the trained immunity-macrophage efferocytosis-CSC axis as a potential target for CSC-directed therapy. However, clinical translation of trained immunity inducers is limited by poor targeting, pharmacokinetic instability, insufficient accumulation, and systemic toxicity. Nanomedicine offers a potential solution by improving cargo stability, tissue retention, controlled release, and macrophage-targeted delivery. In this review, we summarize the molecular links between trained immunity, macrophage efferocytosis, and CSC fate, discuss nanomaterial-based strategies to modulate this axis, and outline the key challenges and future opportunities for developing next-generation antitumor nanomedicines. Unlike previous reviews that discuss these fields separately, this review integrates trained immunity, macrophage efferocytosis and CSC biology into a unified axis, and proposes nanomedicine-enabled TAM reprogramming as a strategy to redirect efferocytic outcomes and suppress CSC-supportive tumor niches.