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한빛사논문
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Proc. Natl. Acad. Sci. USA, Nov 11 2025, 122 (45) | https://doi.org/10.1073/pnas.2409559121
Reprogramming tumor microenvironment via systemic delivery of TLR3 agonist and manganese nanoparticle
Young Seok Choa,b,1, Xingwu Zhoua,1, Xiaoqi Suna,b, Ziye Wana, Julia Crowthera, Mariko Takahashia, Swetha Kodamasimhama, Qi Wua, May Thazin Phooa, Youngseo Nac, Kai Hand, Zaiye Lie, Anna Schwendemana,b, Steven P. Schwendemana,b,f, Yu Leo Leie,g,h, and James J. Moona,b,f,i,2
aDepartment of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109;
bBiointerfaces Institute, University of Michigan, Ann Arbor, MI48109;
cDepartment of Medicinal Chemistry, University of Michigan, Ann Arbor, MI48109;
dState Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China;
eDepartment of Cancer Biology, TheUniversity of Texas MD Anderson Cancer Center, Houston, TX 77030;
fDepartment ofBiomedical Engineering, University of Michigan, Ann Arbor, MI 48109;
gDepartment ofHead and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
hDepartment of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; and
iDepartment of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109
1Y.S.C. and X.Z. contributed equally to this work.
2To whom correspondence may be addressed.
aDepartment of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109;
bBiointerfaces Institute, University of Michigan, Ann Arbor, MI48109;
cDepartment of Medicinal Chemistry, University of Michigan, Ann Arbor, MI48109;
dState Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China;
eDepartment of Cancer Biology, TheUniversity of Texas MD Anderson Cancer Center, Houston, TX 77030;
fDepartment ofBiomedical Engineering, University of Michigan, Ann Arbor, MI 48109;
gDepartment ofHead and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
hDepartment of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; and
iDepartment of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109
1Y.S.C. and X.Z. contributed equally to this work.
2To whom correspondence may be addressed.
Abstract
Toll-like receptor (TLR) agonists, as potent immunostimulatory adjuvants, play a critical role in linking the innate and adaptive immune responses. However, their antitumor effects as cancer immunotherapeutic agents have been limited. Here, we report our finding that manganese ion (Mn2+) potentiates various TLR agonists, leading to robust activation of the TLR pathway and the stimulator of interferon genes (STING) pathway among innate immune cells. In particular, we have observed robust antitumor efficacy after intratumoral administration of a TLR3 agonist and Mn2+. To achieve systemic codelivery of TLR3 agonist and Mn2+, we have developed a low-molecular-weight poly(inosinic:cytidylic acid)-Mn2+ coordination lipid nanoparticle (PLCMP). When administered intravenously in tumor-bearing mice, PLCMP successfully accumulated in tumor, induced innate immune activation, generated tumor-specific T cells, and exerted antitumor efficacy in TLR3- and STING-dependent manner without triggering overt toxicity. Moreover, PLCMP in combination with α-PD-1 therapy achieved long-lasting antitumor efficacy in multiple murine tumor models. Furthermore, vaccination with PLCMP carrying TC-1 tumor antigen peptide elicited strong antigen-specific CD8+ T cell responses and remodeled the tumor microenvironment, resulting in robust therapeutic efficacy. Overall, these results show that simultaneous activation of the TLR3 and STING pathways via PLCMP provides a promising strategy for immunotherapy and vaccination against cancer.
논문정보
- Research article
- 2025년 11월 (BRIC 등록일 2025-11-05)
- 국외 연구진
- 바이오·의료융합 > 바이오·의료융합 기타
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