Park Jee Soo, Jang Won Sik, Lee Myung Eun, Kim Jongchan, Oh Keunhee, Lee Namhee, Ham Won Sik
Department of Urology and Urological Science Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
Department of Urology, Yongin Severance Hospital, Yonsei University Health System, Yongin, Republic of Korea.
Cancer Immunol Immunother. 2025 Aug 6;74(9):282. doi: 10.1007/s00262-025-04139-4.
The therapeutic efficacy of oncolytic vaccinia virus (JX-594) has been demonstrated in metastatic clear cell renal cell carcinoma (ccRCC); however, only selected patients respond, and there are no predictive biomarkers for therapeutic response. We aimed to identify predictive biomarkers for JX-594 treatment and elucidate the underlying mechanisms.
Four cell line-derived xenograft (CDX) models were developed using representative ccRCC cell lines harboring common mutations. Tumors were subcutaneously implanted into the right flank of BALB/c nude mice. Mice were treated with vehicle or JX-594 via intratumoral injection on days 0, 3, and 6, and tumor growth was evaluated. Therapeutic efficacies of JX-594 and a STING agonist were compared in the BAP1-mutant (769-P) CDX model.
All four CDX models showed significant tumor shrinkage following JX-594 treatment versus control. JX-594 exhibited greater efficacy than the STING agonist in BAP1-deficient xenografts. The BAP1 mutation was associated with rapid tumor progression and a stronger response to JX-594. JX-594 induced IFN-β expression through IRF7-dependent signaling in BAP1-deficient cells, bypassing impaired STING-IRF3 signaling.
We identified BAP1 as a potential predictive biomarker for JX-594 treatment and explored its underlying mechanisms. However, given that the study used immunodeficient models, the findings reflect tumor-intrinsic interferon responses and require further validation in immunocompetent models to assess immune microenvironment modulation and clinical relevance.
溶瘤痘苗病毒（JX - 594）在转移性透明细胞肾细胞癌（ccRCC）中的治疗效果已得到证实；然而，只有部分患者有反应，且尚无治疗反应的预测生物标志物。我们旨在确定JX - 594治疗的预测生物标志物并阐明其潜在机制。
使用携带常见突变的代表性ccRCC细胞系建立了四种细胞系来源的异种移植（CDX）模型。将肿瘤皮下植入BALB/c裸鼠的右腹侧。在第0、3和6天通过瘤内注射用赋形剂或JX - 594治疗小鼠，并评估肿瘤生长情况。在BAP1突变（769 - P）CDX模型中比较了JX - 594和一种STING激动剂的治疗效果。
与对照组相比，所有四种CDX模型在接受JX - 594治疗后均显示出明显的肿瘤缩小。在BAP1缺陷的异种移植模型中，JX - 594比STING激动剂表现出更强的疗效。BAP1突变与肿瘤快速进展以及对JX - 594的更强反应相关。JX - 594通过BAP1缺陷细胞中依赖IRF7的信号通路诱导IFN - β表达，绕过了受损的STING - IRF3信号通路。
我们确定BAP1为JX - 594治疗的潜在预测生物标志物并探索了其潜在机制。然而，鉴于该研究使用的是免疫缺陷模型，这些发现反映的是肿瘤内在的干扰素反应，需要在免疫健全模型中进一步验证，以评估免疫微环境调节和临床相关性。
