ArticleCancer discovery2025
NOTCH1 Drives Sexually Dimorphic Immune Responses in Hepatocellular Carcinoma.
Article in Cancer discovery, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Sex-Biased Immunity: The Hidden Variable in Immuno-oncology.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Review
- Efficacy of immune checkpoint inhibitors in female patients with cancer: a systematic review and meta-analysis.Science China. Life sciences · 2026Article
- Purine and pyrimidine-based bacterial cyclic dinucleotides egress the phagosome and activate the innate immune sensor STING.Immunity · 2026Article
- Article
- Global Advances in Hepatocellular Carcinoma Research and Therapy in 2025.Cancer innovation · 2026Review
- Targeting the Notch1-YY1-ICAM1 Signaling Axis Enhances the Efficacy of Immunotherapy in HCC by Activating CD8Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Age and sex: dual drivers remodeling the anti-tumor immune microenvironment and shaping personalized immuno-oncology.Frontiers in immunology · 2026Review
- Overcoming resistance to anti-PD-L1 immunotherapy: mechanisms, combination strategies, and future directions.Molecular cancer · 2025Review
- Single-cell RNA sequencing-derived signatures define response patterns to atezolizumab + bevacizumab in advanced hepatocellular carcinoma.Journal of hepatology · 2025Article
Corrections and comments
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Authors and funding
15 authors.
Funding
Abstract
Hepatocellular carcinoma presents strong sexual dimorphism, being two to three times more frequent in males than in females; however, the role of sex in response to immunotherapies in HCC remains unknown. We demonstrate that NOTCH1, an understudied oncogene in HCC, elicits sexually dimorphic antitumor immunity and response to FDA-approved immunotherapies. Surprisingly, males harboring NOTCH1-driven tumors displayed enhanced antitumor immune responses, which, in mice, were mediated by dendritic and T cells. Conversely, females harboring NOTCH1-driven tumors presented immune evasion and resistance to immunotherapies through a defect in dendritic cell (DC)-mediated priming and activation of CD8+ T cells in mice, which was restored therapeutically with CD40 agonism. Mechanistically, the sexually dimorphic immunity was mediated by genes in the sex chromosomes but not by sex hormones. Together, our study unravels an unexpected association between NOTCH1 and sex in cancer immunity and highlights the potential of restoring the DC-CD8+ T-cell axis with CD40 agonism to improve outcomes. Significance: Although HCC presents strong sexual dimorphism, the role of sex in response to immunotherapies remains elusive. With a novel HCC mouse model and validation in patients with HCC, we demonstrate that NOTCH1 disrupts antitumor immunity specifically in females through a mechanism mediated by sex chromosome genes, which is reversed with CD40 agonism. See related commentary by Zhu and Koltsova, p. 452.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.