HCQ reverses the immune imbalance related to severe infections following chemotherapy of acute myeloid leukemia and exhibits inhibitory effects on inflammatory cytokine storms

Acute myeloid leukemia (AML) is the most prevalent hematological malignancy in adults, characterized by a rapid progression, short clinical course, and poor prognosis. Immune imbalance following severe infections post-chemotherapy represents a critical cause of mortality in AML patients. Our study investigates the effects of hydroxychloroquine (HCQ) on immune imbalance in severe infections after AML chemotherapy and its mechanisms of action on mononuclear macrophage activation and inflammatory cytokine storm models. The findings are expected to provide significant practical implications for both basic research and clinical interventions in managing severe infections in leukemia patients. Our findings indicated that some specific chemokines and cytokines exhibited abnormal increases in AML patients, with more pronounced elevations in severely infected AML patients (AML-SI) compared to uninfected counterparts. HCQ inhibited leukemic cell proliferation and induced apoptosis, although low concentrations demonstrated minimal cytotoxicity. Co-culture of THP-1 cells with bone marrow-derived mesenchymal stem cells (BM-MSCs) from AML patients significantly increased IL-6, IL-8, and TNF-α levels, which were markedly reduced upon HCQ intervention. HCQ exerted limited effects on the CXCL12-CXCR4/7 regulatory axis but induced programmed cell death of leukemic THP-1 cells. RNA-seq showed that the differentially expressed genes in HCQ intervention group were mainly enriched in NOD-like receptor signaling pathway, chemokine signaling pathway, IL-17 signaling pathway, PPAR signaling pathway, NF-κB signaling pathway, and TGF-β signaling pathway. Furthermore, HCQ suppressed monocyte proliferation, enhanced apoptosis, and demonstrated stronger effects on activated mononuclear macrophages. Mechanistically, HCQ regulated Bcl-2 family protein expression, upregulated Bax, activated Caspase-3, and inhibited NLRP3/IL-17A and TLR4/NF-κB signaling pathways, thereby suppressing inflammatory cytokine storms. In all, HCQ effectively reverses immune imbalance and suppresses malignant biological characteristics of leukemic cells, and it also attenuates inflammatory cytokine storms by inhibiting chemokine regulatory axes and suppressing NLRP3/IL-17A and TLR4/NF-κB signaling pathways, offering promising potential for basic research and clinical applications in inflammatory cytokine storm management.