2018
DOI: 10.1038/s41467-018-03225-9
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Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype

Abstract: Resetting tumor-associated macrophages (TAMs) is a promising strategy to ameliorate the immunosuppressive tumor microenvironment and improve innate and adaptive antitumor immunity. Here we show that chloroquine (CQ), a proven anti-malarial drug, can function as an antitumor immune modulator that switches TAMs from M2 to tumor-killing M1 phenotype. Mechanistically, CQ increases macrophage lysosomal pH, causing Ca2+ release via the lysosomal Ca2+ channel mucolipin-1 (Mcoln1), which induces the activation of p38 … Show more

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Cited by 354 publications
(331 citation statements)
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“…For example, macrophages and dendritic cells use lysosomes for microbe killing and antigen processing and presentation. 60 Moreover, CQ has the potential to alleviate pathological conditions associated with increased M2 activity, such as vascular disorder during lung carcinogenesis. 59 Scavenging M2-type macrophages are particularly effective in removing debris from tissues to help resolve inflammation; M2 macrophages have a highly acidic lysosomal pH (<5), whereas M1 macrophages that stimulate immune responses show lower lysosomal acidity (pH >5).…”
Section: Cq Inhibits Lysosomal Acidificationmentioning
confidence: 99%
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“…For example, macrophages and dendritic cells use lysosomes for microbe killing and antigen processing and presentation. 60 Moreover, CQ has the potential to alleviate pathological conditions associated with increased M2 activity, such as vascular disorder during lung carcinogenesis. 59 Scavenging M2-type macrophages are particularly effective in removing debris from tissues to help resolve inflammation; M2 macrophages have a highly acidic lysosomal pH (<5), whereas M1 macrophages that stimulate immune responses show lower lysosomal acidity (pH >5).…”
Section: Cq Inhibits Lysosomal Acidificationmentioning
confidence: 99%
“…[141][142][143] As a mechanism of negative feedback regulation, the IjBa gene is expressed by activated NF-jB. 60 Similarly, the proteasome inhibitor bortezomib induced autophagic degradation of IjBa leading to the activation of NF-jB in diffuse large B-cell lymphoma cells. 146,147 The degree of redundancy of these proteolytic systems in IjBa degradation depends on the cell type and the phase of the inflammatory cascade.…”
Section: Proteostasis Regulates Cellular Stress Responsesmentioning
confidence: 99%
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“…Antimalarial agents, chloroquine (CQ) and hydroxyCQ (HCQ), have been recently studied for their anticancer and antimetastatic activities in different types of malignancies . Preclinical studies in different cancer types show that CQ has multiple complementary mechanisms of action, including inhibition of autophagy, inhibition of oncogenic signaling pathways such as TLR9/NF‐ĸB and CXCL12/CXCR4, normalization of tumor vessels, and modulation of tumor microenvironment . We have previously reported synthesis of CQ‐containing copolymers (pCQ1) by copolymerization of HPMA and methacryloyl‐HCQ (MA‐HCQ).…”
Section: Introductionmentioning
confidence: 99%