Tumor necrosis factor (TNF) has been recognized as an immune activation factor in tumor immunotherapy. Our study demonstrated that TNF blockade markedly enhanced the antitumor efficacy of oncolytic adenovirus (AdV) therapy. To minimize systemic side effects, we engineered a recombinant oncolytic AdV encoding a TNF inhibitor (AdV-TNFi) to confine TNF blockade within the tumor microenvironment (TME). AdV-TNFi significantly improved therapeutic outcomes across various solid tumor models, including four murine and two golden hamster cancers. Immune cell profiling identified CD8+ T cells as the primary mediators of AdV-TNFi-induced antitumor effects, rather than CD4+ T or NK cells. Additionally, AdV-TNFi significantly decreased the infiltration of suppressive myeloid-derived immune cells within the TME and promoted long-term antitumor immune surveillance. Further investigation indicated that TNFR2, more than TNFR1, is pertinent to the immunosuppressive TME, with a recombinant AdV encoding anti-TNFR2 demonstrating comparable antitumor efficacy to AdV-TNFi. Moreover, AdV-TNFi enhanced the antitumor efficacy of gemcitabine and immune checkpoint blockades (ICBs), such as anti-PD-L1 and anti-TIGIT antibodies, in pancreatic carcinoma, and the anti-EGFR antibody in colon carcinoma. In conclusion, intratumoral blockade of the TNF/TNFR2 axis using AdV augments cancer immunotherapy efficacy while mitigating the risks associated with systemic TNF or TNFR2 suppression, warranting further clinical investigation.

中文翻译：

---

通过溶瘤腺病毒原位阻断 TNF-TNFR2 轴可提高实体瘤的抗肿瘤疗效。


肿瘤坏死因子 （TNF） 已被公认为肿瘤免疫治疗中的免疫激活因子。我们的研究表明，TNF 阻断显着增强了溶瘤腺病毒 （AdV） 治疗的抗肿瘤疗效。为了最大限度地减少全身副作用，我们设计了一种编码 TNF 抑制剂 （AdV-TNFi） 的重组溶瘤 AdV，以将 TNF 阻断限制在肿瘤微环境 （TME） 内。AdV-TNFi 显著改善了各种实体瘤模型的治疗结果，包括 4 种小鼠癌和 2 种金仓鼠癌。免疫细胞分析发现 CD8 + T 细胞是 AdV-TNFi 诱导的抗肿瘤作用的主要介质，而不是 CD4 + T 或 NK 细胞。此外，AdV-TNFi 显着减少了 TME 内抑制性髓源性免疫细胞的浸润，并促进了长期抗肿瘤免疫监视。进一步的研究表明，TNFR2 比 TNFR1 更多，与免疫抑制性 TME 相关，编码抗 TNFR2 的重组 AdV 显示出与 AdV-TNFi 相当的抗肿瘤功效。此外，AdV-TNFi 增强了吉西他滨和免疫检查点阻断 （ICB） 的抗肿瘤疗效，例如抗 PD-L1 和抗 TIGIT 抗体，用于胰腺癌，以及抗 EGFR 抗体在结肠癌中的抗肿瘤疗效。总之，使用 AdV 对 TNF/TNFR2 轴进行瘤内阻断可增强癌症免疫治疗疗效，同时降低与全身性 TNF 或 TNFR2 抑制相关的风险，值得进一步临床研究。