Dendritic cell centric nanoengineering couples antigen acquisition and STING activation for cancer immunotherapy
(1) Xiang S (2) Ma S (3) Xu T (4) Yu W (5) Wang J (6) You X (7) Chai M (8) Wang X (9) Wang X (10) Zhang J (11) Liu J (12) Ren X (13) Song W (14) Qin T (15) Li S (16) Wang J
Xiang et al. developed a DC-directed dual pH-gated hybrid nanoparticle (HNP) that sequentially releases αCD47 peptides in the acidic TIME to enhance antigen acquisition and subsequently cGAMP under endosomal acidification to activate intracellular STING. HNP enhanced cDC1 cross-presentation and CD8+ T cell priming, forming CXCL9-enriched cDC1 niches with increased local CD8+ T cell accumulation. HNP suppressed MC38 tumor growth and orthotopic 4T1 metastasis through Batf3-dependent cDC1s and CD8+ T cells, but not macrophages. It also enhanced human DC T cell priming and antitumor activity in a CD34+ humanized xenograft model.
Contributed by Shishir Pant
(1) Xiang S (2) Ma S (3) Xu T (4) Yu W (5) Wang J (6) You X (7) Chai M (8) Wang X (9) Wang X (10) Zhang J (11) Liu J (12) Ren X (13) Song W (14) Qin T (15) Li S (16) Wang J
Xiang et al. developed a DC-directed dual pH-gated hybrid nanoparticle (HNP) that sequentially releases αCD47 peptides in the acidic TIME to enhance antigen acquisition and subsequently cGAMP under endosomal acidification to activate intracellular STING. HNP enhanced cDC1 cross-presentation and CD8+ T cell priming, forming CXCL9-enriched cDC1 niches with increased local CD8+ T cell accumulation. HNP suppressed MC38 tumor growth and orthotopic 4T1 metastasis through Batf3-dependent cDC1s and CD8+ T cells, but not macrophages. It also enhanced human DC T cell priming and antitumor activity in a CD34+ humanized xenograft model.
Contributed by Shishir Pant
ABSTRACT: Stimulator of interferon genes (STING) agonists have shown limited antitumor efficacy, in part because STING activation is not preferentially focused on dendritic cells (DCs), which specialize in cross-priming. We present a DC-centric strategy that synergistically licenses DCs by coordinating CD47-SIRP_ checkpoint relief and STING activation via dual ultra-pH-sensitive gating. Mild tumor acidity first unmasks the _CD47 cue to prime antigen acquisition. Following DC-biased uptake, a second acidic gate releases cGAMP to engage STING in antigen-bearing DCs. Functionally, efficacy requires Batf3-dependent cDC1s and CD8(+) T cells, yet is preserved after macrophage depletion. In murine models, this strategy suppresses tumor growth and metastasis with good tolerability, and it retains activity in a humanized cell-line-derived xenograft model established in NSG-SGM3 hosts, supporting activity in a partially reconstituted human immune setting. Together, this work presents a mechanism-guided combination strategy to optimize STING agonist therapy.
Author Info:
(1) Department of Pharmaceutics, Jiang Su Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009
, China. (2) School of Medicine, Nankai University, Tianjin 300071, China; Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. (3) Department of Pharmaceutics, Jiang Su Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. (4) Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. (5) Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. (6) Tianjin Central Hospital of Obstetrics and Gynecology/Nankai University Affiliated Maternity Hospital, Tianjin Key Laboratory of Human Development and Reproductive Regulation, Tianjin 300100, China. (7) Department of Pharmaceutics, Jiang Su Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. (8) Department of Pharmaceutics, Jiang Su Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. (9) State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Institute of Pharmaceutical Research, 306 Huiren Road, Tianjin 300301, P.R. China. (10) Department of Pharmaceutics, Jiang Su Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. (11) Department of Pharmaceutics, Jiang Su Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. (12) School of Medicine, Nankai University, Tianjin 300071, China; Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. Electronic address: renxiubao@tjmuch.com. (13) Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. Electronic address: wsong@tmu.edu.cn. (14) Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China. Electronic address: qintingting@tjmuch.com. (15) Department of Pharmaceutics, Jiang Su Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: suxin.li@cpu.edu.cn. (16) Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China; Haihe Laboratory of Cell Ecosystem, Tianjin 300100, China. Electronic address: jianwang03@tmu.edu.cn.
Citation: Cell Rep Med 2026 Sep 7 103025 Epub09/07/2026
