Pomalidomide enhances CAR-T cell therapeutic efficacy and remodels immune microenvironment in lymphoid malignancies

Abstract

Background: Chimeric antigen receptor T cell (CAR-T) therapy achieves high remission rates in lymphoid malignancies, but its long-term efficacy is limited by poor persistence and T cell exhaustion. Pomalidomide, an immunomodulatory drug (IMiD), demonstrates clinical synergy with CAR-T therapy, yet the underlying mechanisms driving this potentiation remain poorly defined. This study aimed to elucidate how pomalidomide enhances CAR-T cell function and remodels the immune microenvironment to overcome therapeutic limitations. Methods: In vitro assays (CCK-8, LDH, qPCR, ELISA, flow cytometry) and bulk RNA-seq assessed pomalidomide’s effects on human CAR-T cells. In vivo efficacy was evaluated in myeloma xenograft models. Single-cell RNA sequencing (scRNA-seq) of PBMCs from a lymphoma patient post-CAR-T/pomalidomide assessed immune microenvironment remodeling. Results: Pomalidomide significantly enhanced CAR-T cell proliferation and cytotoxicity in an activation-dependent manner. It upregulated effector molecules (IL-2, IFN-γ) and chemokines (CXCL9-CXCL11), promoted central memory T cells (Tcm), and induced metabolic reprogramming while reducing exhaustion markers. In xenografts, combination therapy induced tumor regression and extended survival vs. CAR-T alone. scRNA-seq revealed pomalidomide-driven remodeling, characterized by increased T/NK cell proportions/activity and reduced myeloid-derived suppressor cell (MDSC) signatures. Conclusions: Pomalidomide synergizes with CAR-T by directly enhancing CAR-T function (memory, cytokine/chemokine production, metabolic fitness, and reduced exhaustion) and remodeling the suppressive immune microenvironment (increased cytotoxic effectors, diminished MDSC activity). These findings provide a crucial mechanistic rationale for optimizing pomalidomide-CAR-T combinations in refractory lymphoid malignancies.