2. Academic Validation
  3. Triple targeting of STING, TGF-β, and PD-L1 boosts CXCL16-CXCR6 signaling for potent antitumor response

Triple targeting of STING, TGF-β, and PD-L1 boosts CXCL16-CXCR6 signaling for potent antitumor response

  • Nat Commun. 2026 Feb 9;17(1):1441. doi: 10.1038/s41467-026-69456-3.
Ming Yi # 1 2,  Tianye Li # 3,  Yinhui Gu # 4,  Mengke Niu 5 6,  Dixuan Xue 7,  Shengtao Hu 7,  Yuze Wu 5,  Bin Zhao 7,  Di Zhang 7,  Yingkang Ma 7,  Minjun Zhang 7,  Jing Zhang 8,  Yongxiang Yan 8,  Pengfei Zhou 8,  Xiaojun Zhang 9,  Zhuxian Zhou 4,  Qian Chu 10,  Kongming Wu 11 12,  Zhijun Dai 13
Affiliations

Affiliations

  • 1 Department of Breast Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, PR China. [email protected].
  • 2 Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China. [email protected].
  • 3 Department of Gynecology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, PR China.
  • 4 Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, PR China.
  • 5 Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
  • 6 Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, PR China.
  • 7 Department of Breast Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, PR China.
  • 8 Wuhan YZY Biopharma Co., Ltd, Wuhan, PR China.
  • 9 Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, PR China.
  • 10 Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China. [email protected].
  • 11 Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China. [email protected].
  • 12 Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, PR China. [email protected].
  • 13 Department of Breast Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, PR China. [email protected].
  • # Contributed equally.
PMID: 41663428 DOI: 10.1038/s41467-026-69456-3
Abstract

Antibodies targeting TGF-β and PD-L1 initially showed promise as second-generation PD-L1 agents. However, consecutive trial failures have limited their clinical success. Our study reveals that the efficacy of the TGF-β×PD-L1 bispecific antibody (BsAb) is compromised by insufficient activation of innate immune responses. To address this, we combine STING agonists with the BsAb, significantly enhancing tumor suppression beyond that achieved with standard STING agonist plus anti-PD-L1 combinations in preclinical models. Unexpectedly, even STING agonist monotherapy is improved by TGF-β blockade, suggesting that TGF-β suppresses STING-driven immune activation. We find that this synergy is mediated by the CXCL16-CXCR6 axis, where STING activation and TGF-β blockade promote CXCL16 expression in macrophages and dendritic cells, recruiting and sustaining cytotoxic CXCR6+ T cells. Additionally, PD-L1 blockade further enhances their antitumor activity. To optimize this strategy, we develop Y101S, an antibody-drug conjugate targeting TGF-β, PD-L1, and STING, which demonstrates superior tumor control and immune modulation in preclinical models. These findings highlight the therapeutic potential of this triple-targeting approach.

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