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<p>Oncolytic vaccinia viruses (OVV) demonstrate the capacity to inflame the tumor microenvironment (TME) and elicit infiltrating tumor-specific T cells responses. However, OVV treatment paradoxically alters the cancer-immune equilibrium within tumors, attenuating anti-tumor immunity and necessitating a deeper understanding of the viral-induced immune landscape to optimize therapeutic potential. This study investigates the impact of single-domain antibody-armed OVs targeting TIM-3 on TME remodeling, aiming to overcome localized immunosuppression and enhance tumor responsiveness to immunotherapeutic interventions. We engineered a tumor-selective OVV vector encoding single-domain antibodies against murine (mNbTIM3) or human (hNbTIM3) TIM-3. The therapeutic efficacy of OVV-mNbTIM3 was evaluated across multiple murine cancer models, demonstrating that localized V<sub>HH</sub>TIM3 delivery via OVV-mNbTIM3 promotes systemic anti-tumor immunity in established cancers. Mechanistically, OVV-mNbTIM3 treatment enhances DCs maturation and tumor-specific CD8<sup>+</sup> T cells activation. Notably, intratumoral expression of hNbTIM3 also conferred therapeutic benefit in humanized mice bearing patient-derived cancer xenografts. These findings provide mechanistic insights for enhancing OVV combination therapies and inform the rational design of next-generation oncolytic viruses with engineered immunomodulatory properties.</p>

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TIM-3 blockade reverses oncolytic vaccinia virus-induced DCs inactivation and T cells exhaustion to improve antitumor immunity and therapeutic efficacy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月25日

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  • Peipei Ye,
  • Yi Wu,
  • Xue Yang,
  • Hui Wu,
  • Yongming Xia,
  • Gongqiang Wu,
  • Gang Cheng,
  • Weidong Sun,
  • Junyu Zhang,
  • Shibing Wang,
  • Xiangmin Tong

摘要

Oncolytic vaccinia viruses (OVV) demonstrate the capacity to inflame the tumor microenvironment (TME) and elicit infiltrating tumor-specific T cells responses. However, OVV treatment paradoxically alters the cancer-immune equilibrium within tumors, attenuating anti-tumor immunity and necessitating a deeper understanding of the viral-induced immune landscape to optimize therapeutic potential. This study investigates the impact of single-domain antibody-armed OVs targeting TIM-3 on TME remodeling, aiming to overcome localized immunosuppression and enhance tumor responsiveness to immunotherapeutic interventions. We engineered a tumor-selective OVV vector encoding single-domain antibodies against murine (mNbTIM3) or human (hNbTIM3) TIM-3. The therapeutic efficacy of OVV-mNbTIM3 was evaluated across multiple murine cancer models, demonstrating that localized VHHTIM3 delivery via OVV-mNbTIM3 promotes systemic anti-tumor immunity in established cancers. Mechanistically, OVV-mNbTIM3 treatment enhances DCs maturation and tumor-specific CD8+ T cells activation. Notably, intratumoral expression of hNbTIM3 also conferred therapeutic benefit in humanized mice bearing patient-derived cancer xenografts. These findings provide mechanistic insights for enhancing OVV combination therapies and inform the rational design of next-generation oncolytic viruses with engineered immunomodulatory properties.