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 Ca ²⁺ release via the lysosomal Ca ²⁺ channel mucolipin-1 (Mcoln1), which induces the activation of p38 and NF-κB, thus polarizing TAMs to M1 phenotype. In parallel, the released Ca ²⁺ activates transcription factor EB (TFEB), which reprograms the metabolism of TAMs from oxidative phosphorylation to glycolysis. As a result, CQ-reset macrophages ameliorate tumor immune microenvironment by decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and Treg cells, thus enhancing antitumor T-cell immunity. These data illuminate a previously unrecognized antitumor mechanism of CQ, suggesting a potential new macrophage-based tumor immunotherapeutic modality.

Abstract

Tumour-associated macrophages (TAMs) display an M2 phenotype that promote tumour immune escape. Here the authors show that Chloroquine (CQ), a lysosome inhibitor used against malaria, inhibits tumour growth by switching TAMs into an M1 tumor-killing phenotype by repolarizing macrophages metabolism.