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

作者：Ming Yi, Tianye Li, Yinhui Gu, Mengke Niu, Dixuan Xue, Shengtao Hu, Yuze Wu, Bin Zhao, Di Zhang, Yingkang Ma, Minjun Zhang, Jing Zhang, Yongxiang Yan, Pengfei Zhou, X Zhang, Zhuxian Zhou, Q. Chu, Kongming Wu, Z. Dai · 发表于：Nature Communications · 年份：2026 · DOI：10.1038/s41467-026-69456-3 · 被引用次数：13 · 研究领域：interferon and immune responses、Cancer Immunotherapy and Biomarkers、Cytokine Signaling Pathways and Interactions

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. The efficacy of the TGF-β×PD-L1 bispecific antibody (BsAb) is not promising clinically. The authors here develop a Y101S, an antibody-drug conjugate targeting TGF-β, PD-L1, and STING, which manifests superior anti-tumor efficacy in preclinical models with the mech...