2. Academic Validation
  3. Simultaneous STING and lymphotoxin-β receptor activation induces B cell responses in tertiary lymphoid structures to potentiate antitumor immunity

Simultaneous STING and lymphotoxin-β receptor activation induces B cell responses in tertiary lymphoid structures to potentiate antitumor immunity

  • Nat Immunol. 2025 Oct;26(10):1766-1780. doi: 10.1038/s41590-025-02259-8.
Junko Sawada # 1,  Yasuhiro Kikuchi # 1,  Maxwell Duah 1,  Jose Luis Herrera 1,  Fumiaki Kanamori 1,  Krisztian Csomos 2 3,  Tomoko Stansel 1,  Nobuyoshi Hiraoka 4,  Masayuki Yoshida 4,  Jolan Walter 2,  Carl F Ware 5,  Masanobu Komatsu 6
Affiliations

Affiliations

  • 1 Cancer and Blood Disorders Institute, Institute for Fundamental Biomedical Research, and Department of Surgery, Johns Hopkins All Children's Hospital, and Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, St. Petersburg, FL, USA.
  • 2 Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
  • 3 Translational Genetics and Genomics Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
  • 4 Division of Pathology and Clinical Laboratories, National Cancer Center Hospital; Division of Molecular Pathology, Analytical Pathology, National Cancer Center Research Institute, Tokyo, Japan.
  • 5 Laboratory of Molecular Immunology, Infectious and Inflammatory Diseases Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 6 Cancer and Blood Disorders Institute, Institute for Fundamental Biomedical Research, and Department of Surgery, Johns Hopkins All Children's Hospital, and Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, St. Petersburg, FL, USA. mkomats1@jhmi.edu.
  • # Contributed equally.
PMID: 40897896 DOI: 10.1038/s41590-025-02259-8
Abstract

B cell-rich tertiary lymphoid structures (TLS) are associated with favorable prognosis and positive response to immunotherapy in Cancer. Here we show that simultaneous activation of innate immune effectors, STING and Lymphotoxin-β receptor (LTβR), results in CD8+ T cell-dependent tumor suppression while inducing high endothelial venule development and germinal center-like B cell responses in tumors to generate functional TLS in a T cell-dependent manner. In a neoadjuvant setting, activation of STING and LTβR by their agonists effectively immunized mice against tumor recurrence, leading to long-term survival. STING activation alone was insufficient for inducing B cell-containing TLS or eliciting long-term therapeutic effects. However, when combined with LTβR activation, it improved the fitness of TLS with B cell expansion and maturation to IgG-producing long-lived plasma cells and memory cells, increased CD4+ T cell recruitment and memory CD8+ T cell expansion, and shifted the TH2/TH17 balance, resulting in the potentiation of humoral and cellular immunity against tumors. These findings suggest a therapeutic approach of simultaneously activating STING and lymphotoxin pathways.

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