Sex disparities in hepatocellular carcinoma immunotherapy: hormonal and genetic influences on treatment efficacy

Abstract

Hepatocellular carcinoma (HCC) is a highly aggressive liver cancer with a rising incidence globally. Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized HCC treatment, yet response rates remain variable. Sex-based disparities in immunotherapy efficacy have become increasingly recognized as important factors influencing treatment outcomes in HCC. This review examines the role of biological sex in HCC progression and immunotherapy responses. It discusses the epidemiology of sex differences in HCC incidence, prognosis, and therapeutic outcomes, highlighting the impact of sex hormones, such as estrogen and testosterone, on immune system function and tumor biology. Estrogen's protective effects, including enhanced T cell activation and improved immune surveillance, contribute to better treatment responses in females, while testosterone's immunosuppressive effects lead to poorer outcomes in males. The review also explores the influence of the tumor microenvironment, including immune cell composition and macrophage polarization, on treatment efficacy. Emerging evidence suggests that sex-specific factors, including hormonal status, should be considered in clinical trials and personalized treatment strategies. By addressing these disparities, tailored immunotherapeutic approaches could optimize efficacy and minimize toxicity in both male and female HCC patients, ultimately improving overall outcomes.

Keywords: estrogen; hepatocellular carcinoma; hormone; immunotherapy; sex disparities.

Figure 1

Molecular mechanisms of estrogen signaling in hepatocellular carcinoma (HCC) progression and immune modulation. (A) YAP signaling and ERα: Estrogen binding to ERα suppresses YAP (Yes-associated protein) signaling in HCC cells. This is achieved by enhancing YAP phosphorylation, preventing its nuclear translocation, and inhibiting downstream oncogenic pathways. The suppression of YAP by ERα contributes to tumor-suppressive effects, highlighting ERα as a potential therapeutic target in HCC. (B) JAK1/STAT3 signaling and ERα: Estrogen binding to ERα modulates the JAK1/STAT3 pathway in HCC cells by stabilizing suppressor of cytokine signaling 3 (SOCS3). Cytokine stimulation activates JAK1, which then phosphorylates STAT3. Phosphorylated STAT3 translocates to the nucleus to regulate target genes involved in inflammation, immune response, and tumor progression. Estrogen’s modulation of this pathway helps control the immune response and liver inflammation, contributing to reduced susceptibility to HCC. Inhibition of STAT3 activation by estrogen enhances anti-tumor immunity and inhibits HCC growth. (C) JAK1/STAT6 signaling and ERβ: In HCC cells, estrogen signaling through ERβ suppresses the JAK1/STAT6 pathway. Cytokine stimulation activates JAK1, which then phosphorylates STAT6, promoting its nuclear translocation and activation of target genes involved in tumor progression and immune suppression. Estrogen’s modulation of the JAK1/STAT6 axis reduces STAT6 activation, leading to a less immunosuppressive tumor microenvironment and enhancing anti-tumor immunity in HCC cells. (D) LCAT signaling and ERα: Estrogen activation of ERα induces the upregulation of lecithin cholesterol acyltransferase (LCAT) in HCC cells, leading to enhanced high-density lipoprotein cholesterol (HDL-C) production. This HDL-C production suppresses cholesterol biosynthesis, inhibiting tumor growth. Furthermore, HDL-C synergizes with lenvatinib, enhancing anti-tumor efficacy. Targeting the LCAT/HDL-C axis may improve immunotherapy and treatment outcomes in HCC.

Figure 2

Testosterone-AR signaling pathway in HCC immunotherapy. (A)Testosterone binds to the androgen receptor (AR) in CD8⁺ T cells, forming a complex in the cytosol. This complex then translocates to the nucleus, where it upregulates the expression of USP18. USP18 inhibits NF-κB activity, reducing IFN-γ production. Additionally, testosterone-AR binding promotes T cell exhaustion, impairing T cell-mediated immunotherapy in HCC. (B) In regulatory T cells (Tregs), the testosterone-AR interaction stabilizes Foxp2, enhancing Treg cell infiltration into the tumor microenvironment (TME). This infiltration suppresses T cell immunotherapy in HCC. (C) In macrophages, the testosterone-AR binding increases the production of IL-10 and TGF-β, which promotes the polarization of macrophages from the M1 to the M2 phenotype. This shift suppresses cytotoxic T cell function, compromising the efficacy of immunotherapy in HCC. (D) In HCC cells, testosterone-AR binding upregulates the transcription of EZH2, resulting in increased levels of H3K27me3. This epigenetic modification silences Wnt signaling inhibitors, thereby activating the Wnt/β-catenin pathway, which promotes cancer cell proliferation and tumor progression. Additionally, AR interacts with mTORC1, which phosphorylates AR at S96 in response to nutrient and mitogenic stimuli. This phosphorylation enhances AR stability, nuclear localization, and transcriptional activity, further promoting lipogenesis, hepatocyte proliferation, and hepatocarcinogenesis.