Sexual dimorphism in liver cancer recurrence: the role of SRY and ischemia-reperfusion injury

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) represent the first and second most common primary liver malignancies, respectively. Despite meaningful advances in diagnostic modalities, systemic therapies, surgical techniques, and expanding transplantation criteria, these cancers continue to impose substantial morbidity and mortality. Curative-intent resection remains the most effective strategy for achieving durable survival; however, postoperative cancer recurrence remains high, with more than 50–70% of patients experiencing recurrence within 2 to 5 years of resection (1,2). Efforts to better characterize tumor biology and uncover mechanisms that drive recurrence are therefore central to improving survival in these deadly malignancies.

The sexual dimorphism of the liver is an increasingly appreciated dimension of liver cancer biology. While men are well known to develop both HCC and iCCA at significantly higher rates than women, emerging data suggest that men also experience worse survival—driven in part by higher recurrence rates even after curative-intent, margin-negative resections (3,4). The biological basis for these differences remains incompletely understood. Some have attributed sex disparities to hormonal influences (5), but therapeutic attempts to modulate these pathways have yielded little clinical benefit (6). A growing body of work instead points toward sex chromosome-linked gene expression as a plausible driver, raising the possibility that male-specific genetic programs may shape the hepatic microenvironment and fundamentally influence ultimate oncologic outcomes (7,8).

It is within this context that the current study by Zhang and colleagues, “Sex Disparity of Liver Cancer Recurrence Following Surgery: Sex Determining Region Y Gene Promotes Immunosuppressive Microenvironment and Favors Metastasis”, makes a particularly important contribution (9). This ambitious investigation builds on the group’s earlier work implicating sex-determining region Y gene (SRY) overexpression in male-predominant liver fibrosis and hepatocarcinogenesis, as well as their demonstration that hepatic ischemia-reperfusion (I/R) injury—which occurs unavoidably during hepatic resection—induces greater hepatic damage in males through SRY upregulation (10-12). The outstanding question, however, has been how SRY and I/R injury interact and whether this interaction influences postoperative tumor biology and recurrence.

The authors first reaffirm, using a rigorously matched, multi-institutional, international cohort of more than 2,300 patients, that male patients with HCC and iCCA experience inferior recurrence-free survival and, in iCCA, worse overall survival compared with matched female counterparts. Although these sex-based disparities have been previously noted, the scale of this cohort, the use of propensity matching, and the incorporation of international data lend a particularly high degree of credibility to these findings.

To investigate the biological underpinnings of these disparities, the authors then employ a previously validated hepatic I/R murine model that mimics the perioperative stress experienced during liver surgery or transplantation. In this model, male mice develop significantly more postoperative tumor recurrences than females—an effect strikingly absent in sham-operated controls. Immune profiling reveals that male livers subjected to I/R accumulate polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and demonstrate relative depletion of CD8⁺ T cells, collectively forming an immunosuppressive tumor microenvironment known to support tumor seeding and outgrowth.

The role of SRY in this process is further clarified as both male and female mice engineered to overexpress SRY exhibit increased recurrence and an immunosuppressive tumor microenvironment after I/R. Conversely, hepatocyte-specific SRY knockout in males reduces recurrence and restores CD8⁺ T-cell infiltration, providing compelling evidence of the effect that SRY has on shaping the postoperative immune milieu. Importantly, these findings are validated in paired human liver specimens obtained before and after reperfusion, demonstrating that male donor livers upregulate SRY following reperfusion and exhibit increased PMN-MDSC recruitment and CD8⁺ T-cell suppression.

Mechanistically, the authors establish that SRY activates NF-κB signaling and induces CXCL1 secretion, a chemokine known to recruit PMN-MDSCs to the injured liver. Pharmacologic inhibition of NF-κB significantly reduces CXCL1 secretion in an SRY-overexpressing human hepatocyte cell line, suggesting that SRY promotes an immunosuppressive microenvironment through an NF-κB-dependent pathway. Although these mechanistic experiments were performed in vitro, the identification of a druggable downstream cascade is a particularly intriguing aspect of this work.

The clinical implications of these findings are substantial. First, this represents one of the clearest mechanistic explanations to date linking male sex, I/R injury, and postoperative liver cancer recurrence. The work further clarifies that surgical stress and SRY expression synergize to create an immunosuppressive microenvironment, as SRY upregulation alone did not increase recurrence in the absence of hepatic I/R. This aligns with emerging evidence in the field: surgical stress appears to fundamentally alter liver physiology in ways that may facilitate metastatic outgrowth. For example, in a murine pancreas cancer model developed by Phipps et al., surgical intervention accelerated the development of metastatic liver lesions, suggesting that surgical stress may prime the liver for tumor colonization (13).

The cell culture findings in this study, which delineate a mechanistic pathway from SRY to NF-κB activation and CXCL1 secretion, also raise intriguing therapeutic possibilities. Although it remains unknown whether targeting this axis can directly reduce recurrence risk, the concept is biologically compelling—particularly as immunomodulatory agents continue to integrate into standard therapeutic strategies in hepatobiliary oncology (14,15). CXCL1-driven recruitment of PMN-MDSCs depletes intratumoral CD8⁺ T cells, whereas immune checkpoint inhibitors function largely by restoring and amplifying CD8⁺ T-cell activity. Agents capable of inhibiting the SRY-NF-κB-CXCL1 pathway may therefore synergize with checkpoint blockade by both limiting immunosuppressive myeloid infiltration and enhancing CD8⁺ T-cell-mediated antitumor responses. Such combination approaches, aimed at reshaping the postoperative microenvironment, may represent a promising direction for future investigation.

The authors acknowledge important limitations of this work. Murine models, while indispensable, cannot fully capture the complexity and heterogeneity of human liver disease. Additionally, it also remains unclear how SRY-driven immune remodeling interacts with the diverse demographic, environmental, and etiologic factors that shape liver cancer biology—including viral hepatitis, alcohol-associated liver disease, metabolic dysfunction, and underlying genetic variation. Moreover, although this study convincingly links SRY to the formation of an immunosuppressive, pre-metastatic niche, the upstream pathways through which hepatic I/R induces SRY upregulation are still poorly understood. Elucidating these mechanisms may represent the next frontier in understanding how surgical stress modulates oncologic outcomes and could be key to disrupting the deleterious interplay between I/R injury and tumor recurrence.

In conclusion, the work by Zhang et al. significantly advances our understanding of how sex influences postoperative oncologic outcomes in primary liver malignancies. By delineating a mechanistic role for SRY in shaping an immunosuppressive hepatic environment after injury, the authors open new avenues for precision oncology in liver surgery and underscore the need to incorporate sex-specific biology into strategies aimed at reducing recurrence and improving survival.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article has undergone external peer review.

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-1-940/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-1-940/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Bowlus CL, Arrivé L, Bergquist A, et al. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology 2023;77:659-702. [Crossref] [PubMed]
2. Singal AG, Llovet JM, Yarchoan M, et al. AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology 2023;78:1922-65. [Crossref] [PubMed]
3. Hu LS, Zhang XF, Weiss M, et al. Recurrence Patterns and Timing Courses Following Curative-Intent Resection for Intrahepatic Cholangiocarcinoma. Ann Surg Oncol 2019;26:2549-57. [Crossref] [PubMed]
4. Zhang H, Han J, Xing H, et al. Sex difference in recurrence and survival after liver resection for hepatocellular carcinoma: A multicenter study. Surgery 2019;165:516-24. [Crossref] [PubMed]
5. Pang C, Li JM, Wang Z, et al. Age-Dependent Female Survival Advantage in Hepatocellular Carcinoma: A Multicenter Cohort Study. Clin Gastroenterol Hepatol 2024;22:305-14. [Crossref] [PubMed]
6. Di Maio M, Daniele B, Pignata S, et al. Is human hepatocellular carcinoma a hormone-responsive tumor? World J Gastroenterol 2008;14:1682-9. [Crossref] [PubMed]
7. Haupt S, Caramia F, Herschtal A, et al. Identification of cancer sex-disparity in the functional integrity of p53 and its X chromosome network. Nat Commun 2019;10:5385. [Crossref] [PubMed]
8. Kido T, Lau YC. The Y-linked proto-oncogene TSPY contributes to poor prognosis of the male hepatocellular carcinoma patients by promoting the pro-oncogenic and suppressing the anti-oncogenic gene expression. Cell Biosci 2019;9:22. [Crossref] [PubMed]
9. Zhang W, Chen LF, Lu Q, et al. Sex disparity of liver cancer recurrence following surgery: sex-determining region Y gene promotes immunosuppressive microenvironment and favors metastasis. Int J Surg 2025;111:7666-76. [Crossref] [PubMed]
10. Dong J, Ke MY, Wu XN, et al. SRY is a Key Mediator of Sexual Dimorphism in Hepatic Ischemia/Reperfusion Injury. Ann Surg 2022;276:345-56. [Crossref] [PubMed]
11. Liu C, Ren YF, Dong J, et al. Activation of SRY accounts for male-specific hepatocarcinogenesis: Implication in gender disparity of hepatocellular carcinoma. Cancer Lett 2017;410:20-31. [Crossref] [PubMed]
12. Wu XN, Wang MZ, Zhang N, et al. Sex-determining region Y gene promotes liver fibrosis and accounts for sexual dimorphism in its pathophysiology. J Hepatol 2024;80:928-40. [Crossref] [PubMed]
13. Phipps JL, English I, Chu J, et al. Abstract C102: Investigating rapid metastatic recurrence of pancreatic cancer after resection in a novel, immune-competent, Myc-dependent murine model. Cancer Res 2024;84:C102. [Crossref]
14. Kelley RK, Ueno M, Yoo C, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2023;401:1853-65. [Crossref] [PubMed]
15. Yau T, Galle PR, Decaens T, et al. Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW): an open-label, randomised, phase 3 trial. Lancet 2025;405:1851-64. [Crossref] [PubMed]