2. Academic Validation
  3. MHC-II-restricted neoantigen vaccine reverses immune microenvironment and overcomes resistance to immune-checkpoint inhibitors in cold tumors

MHC-II-restricted neoantigen vaccine reverses immune microenvironment and overcomes resistance to immune-checkpoint inhibitors in cold tumors

  • Med. 2026 Jan 9;7(1):100936. doi: 10.1016/j.medj.2025.100936.
Xueru Song 1,  Chun Lu 2,  Tao Shi 1,  Hanbing Wang 1,  Wei Liu 2,  Yuting Luo 1,  Xiaoyu Zhou 3,  Yue Wang 1,  Shiji Ren 1,  Lixia Yu 1,  Baorui Liu 1,  Yan Li 4,  Jia Wei 5
Affiliations

Affiliations

  • 1 Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
  • 2 MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University Medical School, Nanjing 210061, China.
  • 3 Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210008, China.
  • 4 Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University Medical School, Nanjing 210061, China; Wuxi Xishan NJU Institute of Applied Biotechnology, Wuxi 214101, China; ChemBioMed Interdisciplinary Research Center at Nanjing University, Nanjing 210061, China. Electronic address: [email protected].
  • 5 Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China; State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, China; ChemBioMed Interdisciplinary Research Center at Nanjing University, Nanjing 210061, China; Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing 211166, China. Electronic address: [email protected].
PMID: 41308654 DOI: 10.1016/j.medj.2025.100936
Abstract

Background: Cold tumors, characterized by poor T cell infiltration and an immunosuppressive tumor microenvironment (TME), are generally resistant to immune-checkpoint inhibitors (ICIs). Although CD4+ T cells play a critical role in anti-tumor immunity, it remains unclear whether major histocompatibility complex (MHC)-II-restricted neoantigen vaccines can reprogram the immunosuppressive TME and overcome ICI resistance.

Methods: Using the B16F10 model, we evaluated the MHC-II-restricted vaccine efficacy, profiled immune responses via flow cytometry and single-cell RNA Sequencing, and identified the potential combination therapy targets poliovirus receptor (PVR) via NicheNet analysis. The combined efficacy was then validated in vitro and in vivo.

Findings: MHC-II-restricted neoantigen vaccine promoted inflammatory signaling within the TME and enhanced infiltration of CD4+ and CD8+ T cells, along with increased interferon (IFN)-γ production and signs of T cell exhaustion, which provided a prerequisite for ICI response. NicheNet analysis revealed enrichment of the inhibitory immune-checkpoint axis PVR-T cell immunoglobulin and ITIM domain (TIGIT) following vaccination. The combination of the vaccines and TIGIT blockade exhibited synergistic anti-tumor efficacy. This combination enhanced cytokine production by antigen-specific T cells, promoted effector memory differentiation, and delayed exhaustion of CD8+ T cells.

Conclusions: MHC-II-restricted neoantigen vaccine remodels the immune inhibitory TME with insufficient T cell infiltration and synergizes with TIGIT blockade to suppress tumor growth, providing a promising combinatorial strategy for cold tumors.

Funding: Supported by the National Key Research and Development Program of China (2023YFC2506400), the National Natural Science Foundation (82373263), and the Fundamental Research Funds for the Central Universities (0214-14380506).

Keywords

MHC-II-restricted neoantigen vaccines; Pre-clinical research; TIGIT antibody; cold tumor; immune-checkpoint inhibitor; tumor microenvironment.

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