The clinical success of CAR-T therapy in hematological malignancies is often undermined by tumor-intrinsic escape mechanisms, notably antigen downregulation and intratumoral heterogeneity. This thesis addresses these bottlenecks by investigating strategies to restore tumor visibility and broaden immune effector functions in B-cell non-Hodgkin lymphoma (B-NHL) and acute myeloid leukemia (AML). In B-NHL, we demonstrated that the Bruton’s tyrosine kinase inhibitor ibrutinib reverses resistance via epigenetic remodeling (decreased DNA methylation and increased H3K4me3) at the CD19 promoter, successfully upregulating surface CD19 density and enhancing cytotoxic efficacy. To circumvent antigenic heterogeneity in AML, we developed an allogeneic CD33-directed invariant Natural Killer T (iNKT) cell platform. Beyond direct lysis, CD33 CAR-iNKT cells induce epitope spreading, reshape the immunological phenotype, and cross-prime conventional CD8+ T cells to eradicate antigen-negative variants. Collectively, these findings provide a comprehensive framework to overcome immune evasion and achieve durable cures.