SYSTEMATIC REVIEW article
Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Novel Roles of SETD2 in Tumor Metabolism and Immunotherapy: A Systematic Review and Meta-Analysis
Chunhui Liu 1
Lei Lin 2
Yonggang Fan 3
1. The First Affiliated Hospital,and College of Clinical Medicine of Henan University of Science and Technology., Luoyang, China
2. Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, China
3. The First Affiliated Hospital,and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
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Abstract
Background: SET domain-containing 2 (SETD2), the sole histone H3 lysine 36 trimethyltransferase, has emerged as a critical tumor suppressor across multiple cancer types. Recent evidence suggests SETD2 orchestrates complex interactions between metabolic reprogramming and immune evasion in the tumor microenvironment. Methods: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)2020 guidelines, we systematically searched PubMed, EMBASE, Web of Science, and Cochrane databases from inception through April 2024. We included studies investigating SETD2's role in tumor metabolism and immunotherapy response. Meta-analysis was performed using random-effects models to assess the association between SETD2 status and clinical outcomes. Protocol was developed a priori but not registered due to the exploratory nature of this emerging field. Results: Of 2,847 initially identified records, 78 studies met inclusion criteria, encompassing approximately 12,400 patients across 12 cancer types. SETD2 loss was associated with metabolic reprogramming (pooled OR: 2.34, 95% confidence interval (CI): 1.89-2.89, p<0.001) and decreased immunotherapy response (hazard ratio (HR): 1.56, 95% CI: 1.32-1.84, p<0.001). Substantial heterogeneity was observed ( I-squared heterogeneity statistic(I²)=52-68%) and explored through subgroup and sensitivity analyses. Mechanistically, SETD2 deficiency promoted glycolytic shift, lipid metabolism dysregulation, and immunosuppressive metabolite accumulation. Furthermore, SETD2 loss correlated with reduced CD8+ T cell infiltration and increased regulatory T cell presence. Conclusions: This meta-analysis identifies SETD2 as an epigenetic regulator linking tumor metabolic reprogramming to antitumor immunity. SETD2 loss was associated with altered metabolic states and reduced clinical benefit from immune checkpoint inhibitors, with the strongest translational relevance observed in ccRCC and substantial evidence in NSCLC and CRC. These findings support further prospective validation and standardized assessment of SETD2, as well as exploration of rational metabolic–immunotherapy combination strategies in SETD2-deficient tumors.
Summary
Keywords
epigenetics, H3K36me3, Immunotherapy, SETD2, Systematic review, tumor metabolism
Received
07 January 2026
Accepted
19 February 2026
Copyright
© 2026 Liu, Lin and Fan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yonggang Fan
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