Kanoda Ryo, Nakajima Shotaro, Okayama Hirokazu, Kaneta Akinao, Chida Shun, Matsumoto Takuro, Saito Katsuharu, Kikuchi Tomohiro, Maruyama Yuya, Suzuki Hiroya, Mimura Kosaku, Saito Motonobu, Hanayama Hiroyuki, Sakamoto Wataru, Momma Tomoyuki, Saze Zenichiro, Kono Koji
Department of Gastrointestinal Tract Surgery, School of Medicine, Fukushima Medical University, Fukushima, Japan.
Department of Multidisciplinary Treatment of Cancer and Regional Medical Support, School of Medicine, Fukushima Medical University, 1 Hikariga-oka, Fukushima, Fukushima, 960-1295, Japan.
Sci Rep. 2025 Jun 2;15(1):19234. doi: 10.1038/s41598-025-03924-6.
The tumor cell-intrinsic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is critical for activating anti-tumor immunity and enhancing immune checkpoint blockade therapy in colorectal cancer (CRC). Cancer-associated fibroblasts (CAFs), key components of the CRC tumor microenvironment, negatively regulate the anti-tumor immune response. However, their impact on tumor cell-intrinsic cGAS-STING expression remains unclear. In the present study, we investigated whether CAFs can downregulate cGAS-STING expression in CRC. We found that cGAS-STING expression in tumor cells inversely correlated with stromal expression of versican (VCAN), an immunosuppressive CAF marker, in CRC tissues. Co-culture experiments using primary human CAFs derived from CRC tissues revealed that CAFs downregulated cGAS and/or STING expression in CRC cell lines (WiDr, LoVo, HCT116). Furthermore, CAFs expressing VCAN and fibronectin 1 appeared to mediate this suppression. These findings suggest that immunosuppressive CAFs contribute to the downregulation of tumor cell-intrinsic cGAS-STING expression in CRC. Therefore, targeting CAFs to restore cGAS-STING expression may represent a promising strategy to enhance the efficacy of CRC treatment.
肿瘤细胞内在的环鸟苷单磷酸-腺苷酸合成酶（cGAS）-干扰素基因刺激因子（STING）通路对于激活抗肿瘤免疫和增强结直肠癌（CRC）的免疫检查点阻断治疗至关重要。癌症相关成纤维细胞（CAF）是CRC肿瘤微环境的关键组成部分，对抗肿瘤免疫反应起负调节作用。然而，它们对肿瘤细胞内在的cGAS-STING表达的影响仍不清楚。在本研究中，我们调查了CAF是否能下调CRC中cGAS-STING的表达。我们发现，在CRC组织中，肿瘤细胞中的cGAS-STING表达与多功能蛋白聚糖（VCAN，一种免疫抑制性CAF标志物）的基质表达呈负相关。使用源自CRC组织的原代人CAF进行的共培养实验表明，CAF下调了CRC细胞系（WiDr、LoVo、HCT116）中cGAS和/或STING的表达。此外，表达VCAN和纤连蛋白1的CAF似乎介导了这种抑制作用。这些发现表明，免疫抑制性CAF有助于下调CRC中肿瘤细胞内在的cGAS-STING表达。因此，靶向CAF以恢复cGAS-STING表达可能是提高CRC治疗疗效的一种有前景的策略。
