Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies

Abstract

Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via β2-adrenergic receptor (β2-AR) activation leads to improved MDSC function through metabolic reprograming, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of Nrf2 and the oxidative stress response, enhancing MDSC survival. Using β2-AR blockade, we target the STAT3 pathway and ATP and itaconate metabolism, disrupting ATP generation by the electron transport chain and decreasing itaconate generation causing diminished MDSC mitochondrial fitness. This disruption increases the response to doxorubicin and could be tested clinically.

Mometasone furoate inhibits tumor progression and promotes apoptosis through activation of the AMPK/mTOR signaling pathway in osteosarcoma

“…Liu et al found that MTERF1 knockdown inhibited colorectal cancer cells proliferation by decreasing in ATP levels and thereby activating p-AMPK/mTOR signaling pathway [29] . A study by Daneshmandi et al showed that induced STAT3 signaling resulted in higher ATP generation, reducing AMPK signalling [30] . Activation of AMPK can inhibit cell growth and proliferation.…”

The Role of Metabolic Reprogramming in the Tumor Immune Microenvironment: Mechanisms and Opportunities for Immunotherapy in Hepatocellular Carcinoma

“…In addition, lactate accumulation enhances IL-6- and GM-CSF-regulated MDSC generation possibly via the Gi-protein-coupled receptor 81 (GPR81)/mTOR/HIF-1α/STAT3 axis [ 21 , 22 ]. By enhancing MCT-4 expression and the glycolytic rate, lactate promotes M2 polarization by inducing arginase-1 (Arg1), HIF-1α, IL-6, and transcriptional repressors such as ICER, which negatively influence anti-tumor responses [ 23 ]. When stimulated by glycolysis and fibronectin 1 (FN-1), HLA-DR- and CD86-high macrophages exhibit a glycolytic phenotype, impeding the secretion of the anti-tumor agent IL-12 p70 through the PKM2/HIF-1α axis [ 24 , 25 ].…”