A dual-function XCL1-CD40L mRNA adjuvant potentiates cancer vaccines by coordinating DC recruitment and maturation

@article{wu2026dualfunction,
  title = {{A dual-function XCL1-CD40L mRNA adjuvant potentiates cancer vaccines by coordinating DC recruitment and maturation}},
  author = {Chunjie Wu and Wanxuan Shao and Yadi Liu and Shuyuan Pan and Wei Wang and Li Deng and Suyue Zhang and Zhimin Cui and Yujiao Wang and Peng He and Yong Yang and Yiheng Zhao},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1875603},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1875603/full},
  note = {CC BY 4.0},
}

TY  - JOUR
TI  - A dual-function XCL1-CD40L mRNA adjuvant potentiates cancer vaccines by coordinating DC recruitment and maturation
AU  - Chunjie Wu
AU  - Wanxuan Shao
AU  - Yadi Liu
AU  - Shuyuan Pan
AU  - Wei Wang
AU  - Li Deng
AU  - Suyue Zhang
AU  - Zhimin Cui
AU  - Yujiao Wang
AU  - Peng He
AU  - Yong Yang
AU  - Yiheng Zhao
PY  - 2026
DA  - 2026/10/14
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1875603
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1875603/full
AB  - Background: Despite the significant promise of mRNA tumor vaccines in treating solid tumors, their clinical response rate is constrained by the low effectiveness of antigen presentation resulting from the immune-suppressive tumor microenvironment (TME). Conventional type 1 dendritic cells (cDC1) are pivotal in antigen cross-presentation; yet, they frequently exhibit insufficient immune-activating communication within solid malignancies.  Methods: This investigation comprehensively examined the functional attributes of cDC1 by TCGA cohorts and single-cell transcriptomic data. Guided by these bioinformatic insights, we engineered and synthesized a dual-functional mRNA adjuvant encoding the mXCL1-mCD40L fusion protein. We assessed the biological functions and anti-tumor efficacy of this adjuvant in combination with Glypican-3 (GPC3) and HPV-associated mRNA vaccines via protein expression, structure prediction, in vivo antigen uptake and presentation assays, antigen-presenting cell activation assays, antigen-specific T cell activation tests, and therapeutic studies in tumor-bearing mouse models.  Results: A high cDC1 signature score was associated with improved overall survival across LIHC and SKCM TCGA cohorts. Compared to normal sample, cDC1s in HCC and melanoma retained their antigen-presentation machinery but received reduced activating ligand inputs (XCL1-XCR1 signaling in HCC and CD40-CD40L signaling in melanoma). AlphaFold 3 showed that the mXCL1-mCD40L fusion protein can maintain structural integrity without spatial steric hindrance. The fusion protein was confirmed to be secreted and to retain both XCL1-dependent chemotactic activity and CD40-dependent dendritic-cell activation. mXCL1-mCD40L mRNA-LNP activated macrophages and dendritic cells in vitro , upregulating immune-related gene expression as confirmed by qPCR. In vivo , the dual-functional adjuvant significantly enhanced the anti-tumor effect of the GPC3 vaccine, outperformed co-delivery of separate mXCL1 and mCD40L mRNA-LNP, and induced stronger specific IFN-γ producing T cells. Meanwhile, this adjuvant also boosted the anti-tumor efficacy of HPV-associated mRNA vaccines. Mechanistically, this adjuvant increased tumor-antigen acquisition and cross-presentation by CD103 ⁺ DCs and promoted DC maturation in draining lymph nodes, accompanied by an increased proportion of peripheral CD8 ⁺ T cells.  Conclusion: By enhancing the recruitment and maturation of cDC1s, the dual-function mXCL1-mCD40L mRNA adjuvant boosts the efficacy of GPC3 and HPV-associated mRNA vaccines, supporting its potential as an antigen-flexible adjuvant platform against solid tumors.
SN  - 1664-3224
ER  -