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Updated: Oct 27, 2025
Macrophage Cholesterol Depletion and Its Effect on the Phagocytosis of Cryptococcus neoformans
Published on: December 19, 2014
Macrophage-Derived Cholesterol Contributes to Therapeutic Resistance in Prostate Cancer
Asmaa El-Kenawi1,2,3, William Dominguez-Viqueira4, Min Liu5
1Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Brian.Ruffell@moffitt.org Asmaa.Elkenawi@moffitt.org.
Abstract:
Castration-resistant prostate cancer (CRPC) is a lethal stage of disease in which androgen receptor (AR) signaling is persistent despite androgen deprivation therapy (ADT). Most studies have focused on investigating cell-autonomous alterations in CRPC, while the contributions of the tumor microenvironment are less well understood. Here we sought to determine the role of tumor-associated macrophages in CRPC, based upon their role in cancer progression and therapeutic resistance. In a syngeneic model that reflected the mutational landscape of CRPC, macrophage depletion resulted in a reduced transcriptional signature for steroid and bile acid synthesis, indicating potential perturbation of cholesterol metabolism. As cholesterol is the precursor of the five major types of steroid hormones, we hypothesized that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Macrophage depletion reduced androgen levels within prostate tumors and restricted AR nuclear localization in vitro and in vivo. Macrophages were also cholesterol-rich and were able to transfer cholesterol to tumor cells in vitro. AR nuclear translocation was inhibited by activation of liver X receptor (LXR)-β, the master regulator of cholesterol homeostasis. Consistent with these data, macrophage depletion extended survival during ADT and the presence of macrophages correlated with therapeutic resistance in patient-derived explants. Taken together, these findings support the therapeutic targeting of macrophages in CRPC. SIGNIFICANCE: These results suggest that macrophage-targeted therapies can be combined with androgen deprivation therapy to treat patients with prostate cancer by limiting cholesterol bioavailability and the production of intratumoral androgens.See related commentary by Al-Janabi and Lewis, p. 5399.
Insights
Tumor-associated macrophages fuel castration-resistant prostate cancer (CRPC) by supplying cholesterol for androgen production. Targeting macrophages may improve androgen deprivation therapy (ADT) outcomes in CRPC patients.
Area of Science:
- Oncology
- Immunology
- Endocrinology
Background:
- Castration-resistant prostate cancer (CRPC) persists despite androgen deprivation therapy (ADT), often driven by androgen receptor (AR) signaling.
- The tumor microenvironment's role in CRPC progression and therapeutic resistance is less understood than cell-autonomous alterations.
- Tumor-associated macrophages (TAMs) are implicated in cancer progression and resistance, prompting investigation into their role in CRPC.
Purpose of the Study:
- To determine the role of TAMs in CRPC, specifically their contribution to androgen biosynthesis and AR signaling.
- To investigate if TAMs regulate cholesterol metabolism and androgen production within the prostate tumor microenvironment.
- To evaluate the therapeutic potential of targeting macrophages in CRPC.
Main Methods:
- Utilized a syngeneic CRPC model reflecting the disease's mutational landscape.
- Employed macrophage depletion strategies and assessed transcriptional signatures related to steroid and bile acid synthesis.
- Measured androgen levels, AR nuclear localization, and cholesterol transfer between macrophages and tumor cells in vitro and in vivo.
- Investigated the effect of liver X receptor (LXR)-β activation on AR nuclear translocation and evaluated macrophage presence in patient-derived explants.
Main Results:
- Macrophage depletion reduced steroid and bile acid synthesis signatures, suggesting altered cholesterol metabolism.
- Macrophage depletion decreased intratumoral androgen levels and inhibited AR nuclear localization.
- Macrophages were cholesterol-rich and transferred cholesterol to tumor cells; LXR-β activation inhibited AR nuclear translocation.
- Macrophage depletion prolonged survival during ADT, and macrophage presence correlated with therapeutic resistance in patient samples.
Conclusions:
- TAMs play a critical role in CRPC by supplying cholesterol, thereby regulating intratumoral androgen biosynthesis and AR signaling.
- Targeting macrophages can disrupt cholesterol homeostasis and androgen production, offering a novel therapeutic strategy for CRPC.
- Combining macrophage-targeted therapies with ADT holds promise for improving treatment outcomes in prostate cancer patients.
