Novel roles of SETD2 in tumor metabolism and immunotherapy: a systematic review and meta-analysis

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 (I 2 ) = 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. Conclusion 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.