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Published on: September 9, 2011
Ferroptosis-STING co-activation drives GzmB+CD38+CD8+ T-cell expansion to overcome lymphoma immunosuppression
Xiongjie Zhu1, Donghui Zhang2, Jing Zhang3
1Department of Medical Oncology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China.
The immunosuppressive tumor microenvironment (TME) of B-cell lymphoma limits the efficacy of conventional chemotherapy and hampers the full activation of antitumor immunity. Here, we report a tumor cell membrane-camouflaged nanoplatform (CM@HFeS/DOX/MSA-2) that couples ferroptosis amplification with cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation to overcome these barriers. The HFeS nanozyme promotes lipid peroxidation (LPO) and reactive oxygen species (ROS) generation, while doxorubicin (DOX) augments immunogenic cell death (ICD) and facilitates cytosolic DNA accumulation, thereby potentiating MSA-2-mediated STING activation. In vitro and in vivo, CM@HFeS/DOX/MSA-2 synergistically induces ferroptosis, enhances ICD hallmarks, and drives robust dendritic cell (DC) maturation. In an A20 B-cell lymphoma model, this biomimetic nanoplatform markedly suppresses tumor growth, increases intratumoral CD8+ T-cell and DC infiltration, and reduces immunosuppressive macrophages. Imaging mass cytometry and transcriptomic profiling further identify granzyme B (GzmB)+CD38+CD8+T cells and major histocompatibility complex class II (MHCII)+CD103+ CD4+T cells as key effector populations within the remodeled TME. Immune cell depletion experiments support a critical role for CD8+ T cells and the DC-associated immune axis in mediating therapeutic efficacy. Moreover, CM@HFeS/DOX/MSA-2 sensitizes tumors to anti-programmed cell death protein 1 (PD-1) checkpoint blockade and confers strong vaccine-like protection in tumor rechallenge models. Together, this study presents a rationally engineered nanoplatform that coordinately activates ferroptosis and cGAS-STING signaling to reprogram the lymphoma immune landscape and achieve robust, durable antitumor immunity.
The immunosuppressive tumor microenvironment (TME) of B-cell lymphoma limits the efficacy of conventional chemotherapy and hampers the full activation of antitumor immunity. Here, we report a tumor cell membrane-camouflaged nanoplatform (CM@HFeS/DOX/MSA-2) that couples ferroptosis amplification with cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation to overcome these barriers. The HFeS nanozyme promotes lipid peroxidation (LPO) and reactive oxygen species (ROS) generation, while doxorubicin (DOX) augments immunogenic cell death (ICD) and facilitates cytosolic DNA accumulation, thereby potentiating MSA-2-mediated STING activation. In vitro and in vivo, CM@HFeS/DOX/MSA-2 synergistically induces ferroptosis, enhances ICD hallmarks, and drives robust dendritic cell (DC) maturation. In an A20 B-cell lymphoma model, this biomimetic nanoplatform markedly suppresses tumor growth, increases intratumoral CD8+ T-cell and DC infiltration, and reduces immunosuppressive macrophages. Imaging mass cytometry and transcriptomic profiling further identify granzyme B (GzmB)+CD38+CD8+T cells and major histocompatibility complex class II (MHCII)+CD103+ CD4+T cells as key effector populations within the remodeled TME. Immune cell depletion experiments support a critical role for CD8+ T cells and the DC-associated immune axis in mediating therapeutic efficacy. Moreover, CM@HFeS/DOX/MSA-2 sensitizes tumors to anti-programmed cell death protein 1 (PD-1) checkpoint blockade and confers strong vaccine-like protection in tumor rechallenge models. Together, this study presents a rationally engineered nanoplatform that coordinately activates ferroptosis and cGAS-STING signaling to reprogram the lymphoma immune landscape and achieve robust, durable antitumor immunity.
