Chemo-drugs in cell microparticles reset antitumor activity of macrophages by activating lysosomal P450 and nuclear hnRNPA2B1

Abstract

Macrophages in tumors (tumor-associated macrophages, TAMs), a major population within most tumors, play key homeostatic functions by stimulating angiogenesis, enhancing tumor cell growth, and suppressing antitumor immunity. Resetting TAMs by simple, efficacious and safe approach(s) is highly desirable to enhance antitumor immunity and attenuate tumor cell malignancy. Previously, we used tumor cell-derived microparticles to package chemotherapeutic drugs (drug-MPs), which resulted in a significant treatment outcome in human malignant pleural effusions via neutrophil recruitments, implicating that drug-MPs might reset TAMs, considering the inhibitory effects of M2 macrophages on neutrophil recruitment and activation. Here, we show that drug-MPs can function as an antitumor immunomodulator by resetting TAMs with M1 phenotype and IFN-β release. Mechanistically, drug molecules in tumor MPs activate macrophage lysosomal P450 monooxygenases, resulting in superoxide anion formation, which further amplifies lysosomal ROS production and pH value by activating lysosomal NOX2. Consequently, lysosomal Ca2+ signaling is activated, thus polarizing macrophages towards M1. Meanwhile, the drug molecules are delivered from lysosomes into the nucleus where they activate DNA sensor hnRNPA2B1 for IFN-β production. This lysosomal-nuclear machinery fully arouses the antitumor activity of macrophages by targeting both lysosomal pH and the nuclear innate immunity. These findings highlight that drug-MPs can act as a new immunotherapeutic approach by revitalizing antitumor activity of macrophages. This mechanistic elucidation can be translated to treat malignant ascites by drug-MPs combined with PD-1 blockade.

Harnessing innate immune pathways for therapeutic advancement in cancer

“…Interestingly, the induced IFN-β enhanced CTLs’ PD-1 expression, showing significant benefits in combination with PD-1 inhibitors and suggesting the potential advantages of hnRNPA2B1 agonists in tumors resistant to ICB therapy. 524 …”

Role of Heterogeneous Nuclear Ribonucleoproteins in the Cancer-Immune Landscape

“…Recent findings also suggest a favorable role of hnRNP as a target for immunotherapy [ 171 ]. A recent study using methotrexate packaged in tumor-derived particles switched the macrophage phenotype from immunosuppressive M2 to proinflammatory M1 by activating lysosomal P450 monooxygenases and IFN-β production through hnRNPA2/B1 [ 172 ]. HnRNPL knockdown reduced the expression of programmed death ligand (PDL)-1 in prostate cancer, which sensitized cancer cells to T cell infiltration and anti-PD-1 therapy [ 173 ].…”

Challenges and Opportunities for Extracellular Vesicles in Clinical Oncology Therapy

“…Based on this information, we found that the GTP-binding protein (guanosine triphosphate-binding protein) that mediates lysosomal transport, the Rab7 protein (Ras-related GTP-binding protein 7), is anchored on the lysosomal membrane after binding to GTP, and through this effector molecule RILP (Rab7-interacting lysosomal protein), the dynein is recruited to the lysosome, and once it reaches the lysosomal membrane, the dynein aggregates to form the Rab7 dynein complex, which acts as a link between the lysosome and microtubules. Lysosomal dynein is introduced into the nucleus along the microtubules, and then the drug is released near the nucleus and enters the nucleus through nuclear pores [ 54 ] ( Figure 2 ). Based on this mechanism, T-MPs could be widely used as chemosensitizers to improve the chemotherapeutic effect of NMIBC in this way.…”

“… Drug-loaded T-MPs deliver drugs into the nucleus based on [ 54 ] (Signal transduction and targeted therapy, 2023). …”

“…This process may promote P450-driven lysosomal ROS production, which, in turn, activates the lysosomal NOX2 (NADPH oxidase 2) system, thereby increasing ROS production. Therefore, the pH of the lysosome rises and Ca 2+ is released ( Figure 2 ) [ 54 ]. As a result of this molecular transformation, T-MPs used for drug packaging have the capacity to polarize M2 macrophages into M1 macrophages, suggesting that the effect of T-MPs on macrophage phenotype may be more than a single M2-type polarization, but a complex mixed phenotype.…”