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. 2023 Aug 28;20(8):568-574.
doi: 10.20892/j.issn.2095-3941.2023.0256.

Expanding horizons in overcoming therapeutic resistance in castration-resistant prostate cancer: targeting the androgen receptor-regulated tumor immune microenvironment

Bisheng Cheng  1 , Hai Huang  1
Affiliations

Expanding horizons in overcoming therapeutic resistance in castration-resistant prostate cancer: targeting the androgen receptor-regulated tumor immune microenvironment

Bisheng Cheng et al. Cancer Biol Med. .
No abstract available

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Conflict of interest statement

No potential conflicts of interest are disclosed.

Figures

Figure 1
Figure 1
Illustration of the androgen receptor (AR) genomic pathway. ① Elevated AR expression combined with continuous production of steroids by the tumor. ② Non-specific binding and activation of mutant AR by alternative ligands, including estrogen (E2), progesterone (P), glucocorticoids (G), and flutamide (F). ③ Ligand-independent mechanisms of AR activation involve the Akt, HER2, and Ack1 kinases, which lead to AR phosphorylation, as well as long non-coding RNAs (e.g., PCGEM1), which bind AR and enhance the transcription of genes targeted by AR. ④ AR-independent pathways contributing to cancer cell survival and growth, mediated by Stat3 signaling or upregulation of anti-apoptotic Bcl-2. The glucocorticoid receptor (GR) activates a similar set of AR target genes critical for cancer cell survival.
Figure 2
Figure 2
Illustration of AR-mediated repression of IL-1β and effects on the TME. The figure illustrates the role of AR as a transcriptional repressor of IL-1β in tumor-associated macrophages (TAMs). In the absence of androgen deprivation therapy (ADT), AR restrains the expression and secretion of IL-1β in TAMs, thereby maintaining immune homeostasis within the tumor microenvironment (TME). After ADT, AR’s inhibition of IL-1β is alleviated, thus resulting in excessive expression and secretion of IL-1β in TAMs, and establishing an immune suppressive microenvironment.
Figure 3
Figure 3
Illustration of AR regulation of tumor-infiltrating CD8+ T cell activity and stemness. The AR inhibits the activity of male tumor-infiltrating CD8+ T cells, thus resulting in decreased effector function and impaired cytotoxicity against tumor cells. In addition, the AR negatively affects the stemness of CD8+ T cells, thereby decreasing self-renewal capability and compromising long-term persistence within the tumor microenvironment.
See this image and copyright information in PMC

References

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    1. Wang D, Cheng C, Chen X, Wang J, Liu K, Jing N, et al. IL-1beta is an Androgen-Responsive target in macrophages for immunotherapy of prostate cancer. Adv Sci (Weinh) 2023;10:e2206889. - PMC - PubMed
    1. Toniutto P, Shalaby S, Mameli L, Morisco F, Gambato M, Cossiga V, et al. Role of sex in liver tumor occurrence and clinical outcomes: a comprehensive review. Hepatology. 2023 [Online ahead of print] - PubMed

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