Genetic and epigenetic modulation of CAR T-cell responses: A systematic review exploring the influence of host genetic variations and epigenetic modifications on CAR T-cell therapy outcomes.

e15197 Background: Chimeric antigen receptor (CAR) T-cell therapy demonstrates variable efficacy in hematological malignancies (complete response rates: 50-90%), partially attributable to host T-cell characteristics present before manufacturing. This review examines T-cell intrinsic genetic variants and epigenetic states that influence CAR-T expansion, persistence, and anti-tumor function. Methods: This systematic review followed PROSPERO-registered protocol (CRD42024548616).PubMed, Embase, and Scopus were systematically searched through April 2025, identifying 25 eligible studies wherein CAR-T targets included CD19 and GD2. Epigenetic interventions covered DNA methyltransferase inhibitors and histone deacetylase inhibitors; genetic profiling included whole-exome sequencing or targeted mutation panels. Quality was assessed using Cochrane Risk of Bias 2, Newcastle-Ottawa Scale, and ROBINS-I tools. GRADE framework was used to evaluate evidence certainty. Results: Evidence quality ranged from low to very low (GRADE assessment). Pre-infusion DNA methylation at 54 CpG sites associated with CD19 CAR-T outcomes in one chronic lymphocytic leukemia cohort (hazard ratio for event-free survival 0.12, 95% CI 0.03-0.51, n = 43), with partial validation in B-cell acute lymphoblastic leukemia/non-Hodgkin lymphoma (n = 24) but contradictory null findings in diffuse large B-cell lymphoma (n = 2 studies). Decitabine treatment during manufacturing reprogrammed T cells from Th2 toward Th1 phenotype (7 experimental studies; standardized mean difference 1.24, 95% CI 0.78-1.70) but showed no survival benefit in one phase 1/2 clinical trial (n = 32). Cytotoxicity of CAR-T cells in vitro was enhanced by histone deacetylase inhibitors (6/6 preclinical studies),clinical outcomes didn't improve and failed during post-infusion (tucidinostat trial, n = 32). TET2-mutant CAR-T products demonstrated enhanced complete response rates in chronic lymphocytic leukemia (54% vs. 12%, p < 0.01, n = 43) but not in diffuse large B-cell lymphoma (2 null studies). In solid tumor models (3 preclinical studies), tumor-associated macrophage M2 polarization and myeloid-derived suppressor cell infiltration correlated with reduced CAR-T expansion (correlation coefficients -0.62 to -0.74), though causality was not established. Conclusions: T-cell intrinsic genetic and epigenetic factors show associations such as very low certainty evidence, (GRADE ⊕⊝⊝⊝). However, effect sizes are modest, findings are inconsistent across disease, and clinical translation faces manufacturing timeline constraints. Pre-specified methylation panels, standardized profiling platforms, and manufacturing-integrated epigenetic interventions are required before these biomarkers can guide better therapeutic optimization.