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 anti-tumor immunity. A better understanding of how different chemotherapy modes mediate antitumor immune responses could provide insights for developing optimized treatment modalities. Here, we demonstrated that metronomic chemotherapy, a mode of frequent and regular administration of chemotherapeutic drugs at lower doses, induced robust CD8+ T cell-dependent anti-tumor immune memory by modulating activity of mature regulatory dendritic cells (mregDCs). Mechanistically, by imposing more frequent stress on tumor cells, metronomic chemotherapy induced sustained activation of 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 on mregDCs, inhibiting AXL kinase activity and downregulating 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.