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Review
. 2024 May 28:15:1416941.
doi: 10.3389/fimmu.2024.1416941. eCollection 2024.

Sex differences in cancer and immunotherapy outcomes: the role of androgen receptor

Junzhe Zhao #  1   2 , Qian Wang #  2   3 , Alexandra F Tan  4 , Celestine Jia Ling Loh  1   5 , Han Chong Toh  2
Affiliations
Review

Sex differences in cancer and immunotherapy outcomes: the role of androgen receptor

Junzhe Zhao et al. Front Immunol. .

Abstract

Across the wide range of clinical conditions, there exists a sex imbalance where biological females are more prone to autoimmune diseases and males to some cancers. These discrepancies are the combinatory consequence of lifestyle and environmental factors such as smoking, alcohol consumption, obesity, and oncogenic viruses, as well as other intrinsic biological traits including sex chromosomes and sex hormones. While the emergence of immuno-oncology (I/O) has revolutionised cancer care, the efficacy across multiple cancers may be limited because of a complex, dynamic interplay between the tumour and its microenvironment (TME). Indeed, sex and gender can also influence the varying effectiveness of I/O. Androgen receptor (AR) plays an important role in tumorigenesis and in shaping the TME. Here, we lay out the epidemiological context of sex disparity in cancer and then review the current literature on how AR signalling contributes to such observation via altered tumour development and immunology. We offer insights into AR-mediated immunosuppressive mechanisms, with the hope of translating preclinical and clinical evidence in gender oncology into improved outcomes in personalised, I/O-based cancer care.

Keywords: sex; androgen receptor; gender oncology; immunotherapy; tumour microenvironment.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
(A, B) Top 10 most common cancers worldwide (all ages and sexes) by incidence (A) and mortality (B), plotted on the Global Cancer Observatory (GCO) platform (14). (C) The incidence and mortality of the 7 sex-neutral cancers in the top 10, females versus males. (D) Male/Female ratios of incidence (blue) and mortality (red) of the 7 cancers. Data from GLOBOCAN2020.
Figure 2
Figure 2
Top 10 most common cancers worldwide by incidence, females (A) versus males (B), plotted on the GCO platform (14). Data from GLOBOCAN 2020.
Figure 3
Figure 3
AR and ER signalling pathways in different cancer cells. ER and AR share similar structures, and they compete in each other’s signalling pathways. In ER+ breast cancer cells, AR substitutes ER on ERE and stops downstream transcription, eliciting an antitumor effect. ER and AR also share the same co-activator FOXA1 on ERE. In LAR breast cancer and prostate cancer, enzalutamide competes with androgen to stop AR activation. (Created with BioRender.com).
Figure 4
Figure 4
Summary of the effect of AR on different cell types in the TME. (Created with BioRender.com).
See this image and copyright information in PMC

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