Single-Stranded RNA Origami Remodels Macrophage to Promote the Synergistic Antitumor Effect with 5‑Fluorouracil in Pancreatic Cancer

The advancement of cancer immunotherapy has focused on
developing
therapies that not only target tumor progression but also enhance
immune responses, which could potentially shift the balance within
the tumor microenvironment (TME) to promote a more immune-competent
environment and improve the effectiveness of antitumor immunotherapies.
This study evaluates the internalization of single-stranded RNA origami
(ssRNAOG) in coculture models mimicking the TME in vitro and the antitumor
efficacy of the combination of ssRNAOG with 5-fluorouracil (5-FU)
in pancreatic ductal adenocarcinoma (PDAC) models. The internalization
of ssRNAOG triggers the TLR3 signaling pathway, leading to robust
innate immune activation. Notably, ssRNAOG induces the overexpression
of MHC class I protein on macrophages, which recruits NK cells into
the TME. The combination of ssRNAOG and 5-FU significantly suppressed
tumor cell colony formation in vitro, demonstrating a synergistic
antiproliferative effect. Transcriptomic and proteomic analyses revealed
a significant upregulation of inflammatory cytokines and the activation
of NF-κB and STAT1, which are indicative of M1-like polarization
in macrophages. In vivo administration of both ssRNAOG and 5-FU revealed
a marked reduction in tumor burden and an extension of survival in
mice bearing xenograft PDAC tumors. Immunohistochemistry revealed
a shift in macrophage polarization toward the M1-like phenotype, which
is associated with enhanced proinflammatory responses and reduced
tumor proliferation. These findings indicate that ssRNAOG, as a potent
modulator of the TME that can sensitize resistant tumors to chemotherapy,
presents a novel immunotherapeutic strategy for PDAC.