Abstract Background: Adoptive cell transfer-based immunotherapies have shown limited efficacy against most solid tumors. A key barrier to success is the immunosuppressive tumor microenvironment (TME). Beyond local effects, tumors induce systemic immune disturbances that further hinder anti-tumor immunity and promote disease progression. In this study, we investigate how tumor-driven systemic immunosuppression compromises the function of both endogenous and adoptively transferred natural killer (NK) cells, identifying potential strategies to enhance immunotherapeutic outcomes. Study Design: We utilized syngeneic murine cancer models to systematically characterize alterations in immune cell populations within the circulation and spleen. Comprehensive and in-depth assessment of immune cell function, transcriptional activity, and metabolic state was performed using flow cytometry, Seahorse metabolic analysis, RNA sequencing, metabolic tracing, and ex vivo co-culture systems. Results: In our PDAC mouse models, tumor burden elicited a robust systemic inflammatory response marked by expansion of myeloid lineage cells, particularly MDSCs, within the TME, peripheral blood, and spleen. Tumor growth led to reduced frequencies and functional deficits in both endogenous and adoptively transferred NK cells in circulation and spleen. Depletion of Gr-1+ MDSCs effectively restored NK cell effector functions. Mechanistic analyses demonstrated that MDSCs in tumor-bearing mice promote NK cell dysfunction through induction of lipid peroxidation. Notably, we observed pronounced upregulation of apolipoprotein E (ApoE)—a central lipid metabolism regulator—in MDSCs, which drove increased lipid oxidation and reactive oxygen species (ROS) production. Disruption of the ApoE-LDL receptor (LDLR) axis in MDSCs, achieved via genetic ablation, reprogrammed their metabolic activities and significantly reduced their immunosuppressive capacity toward both endogenous and transferred NK cells. Furthermore, pharmacological inhibition of lipid utilization rescued NK cell function and, when combined with NK cell adoptive transfer, produced synergistic anti-tumor effects in PDAC models. Conclusions: Our results emphasize the pivotal role of MDSC expansion in mediating systemic immunosuppression in tumor-bearing hosts. We identify the ApoE/LDLR axis as a promising therapeutic target to disrupt MDSC-driven immunosuppression, thereby enhancing the efficacy of NK cell–based immunotherapies. These findings underscore the importance of resolving systemic immune dysregulation in cancer patients to maximize the benefits of immunotherapy. Citation Format: Chao Xu, Hongyuan Chen, Liangjie Chi, Fangqin Xue, Chunbo He. Targeting the ApoE-LDLR pathway disrupts MDSC-mediated systemic immunosuppression and enhances the efficacy of NK cell immunotherapy abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Mechanisms of Cancer Immunity and Cancer-related Autoimmunity; 2025 Sep 24-27; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(9 Suppl):Abstract nr PR-01.
Chao et al. (Wed,) studied this question.