Metronomic Chemotherapy Induces Metabolic Reprogramming in Cancer Cells That Modulates Mature Regulatory Dendritic Cell Function to Stimulate Antitumor Immunity

The efficacy of chemotherapy depends partly on the ability to induce antitumor immunity. A better understanding of how different chemotherapy modes mediate antitumor immune responses could provide insights for developing optimized treatment modalities. In this study, we demonstrated that metronomic chemotherapy (MC), a mode of frequent and regular administration of chemotherapeutic drugs at lower doses, induced robust CD8+ T cell-dependent antitumor immune memory by modulating the activity of mature regulatory dendritic cells (mregDCs). Mechanistically, by imposing more frequent stress on tumor cells, MC induced sustained activation of activating transcription factor 4 (ATF4), leading to metabolic reprogramming of tumor cells and enhanced asparagine (Asn) release into the tumor microenvironment. Functioning as a ligand, Asn directly bound to AXL receptor tyrosine kinase (AXL) on mregDCs, inhibiting AXL kinase activity and downregulating programmed death-ligand 1 (PD-L1) expression. Consequently, mregDCs with reduced PD-L1 expression fostered the generation of more memory-like CD8+ T cells during their interactions. Overall, this study unveils critical biological events driving antitumor immune memory formation under therapeutic stress and provides a rationale for optimizing chemotherapy modalities. SIGNIFICANCE: Metronomic chemotherapy enhances antitumor immunity by rewiring tumor cell metabolism to reprogram mature regulatory dendritic cells and foster memory CD8+ T-cell formation, providing insights for enhancing treatment efficacy.