Faculty, Staff and Student Publications

Language

English

Publication Date

11-11-2025

Journal

Proceedings of the National Academy of Sciences of the United States of America

DOI

10.1073/pnas.2409559121

PMID

41183207

PMCID

PMC12626007

PubMedCentral® Posted Date

11-3-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Animals, Toll-Like Receptor 3, Tumor Microenvironment, Manganese, Mice, Nanoparticles, Immunity, Innate, Cell Line, Tumor, Mice, Inbred C57BL, Female, Humans, Immunotherapy

Published Open-Access

yes

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