Guerrero Claudia, Casal Marta, Alierta Cristina, Moreo Eduardo, Araujo-Voces Miguel, Uranga Santiago, Gómez Ana Belén, Martín Carlos, Aguiló Nacho
Grupo de Genética de Micobacterias, Departamento de Microbiología y Medicina Preventiva, Facultad de Medicina, Universidad de Zaragoza, IIS-Aragon, Zaragoza, Spain.
CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain.
Cancer Gene Ther. 2025 Aug 2. doi: 10.1038/s41417-025-00948-y.
Lung metastases frequently arise from primary tumors, including bladder cancer, and represent a critical negative prognostic factor. Natural Killer (NK) cells have shown to play a vital role in controlling metastasis. Consequently, tumor cells have evolved specific mechanisms to evade NK cell-mediated immune surveillance, promoting metastasis and resistance to immunotherapy. In this study, we investigated the prophylactic and therapeutic potential of intravenous Bacillus Calmette-Guerin (BCG) in preventing lung metastases from bladder cancer cells using a murine model. We demonstrated that prophylactic BCG administration significantly reduced tumor burden and prolonged survival, largely through NK cell activation. However, BCG treatment was ineffective when administered over established tumors, likely due to tumor-driven immune evasion mechanisms. Our results revealed the contribution of interferon-gamma (IFN-γ) to tumor resistance. Tumor cells exposed to IFN-γ were more resistant to BCG in vivo, which correlated with the overexpression of immune checkpoint molecules, whereas disruption of the IFN-γ signaling pathway in tumor cells partially restored the therapeutic efficacy of BCG. Our findings highlight the importance of understanding tumor immune escape mechanisms and suggest that BCG could be a promising treatment for preventing lung metastases in bladder cancer.
肺转移瘤常起源于原发性肿瘤，包括膀胱癌，是一个关键的不良预后因素。自然杀伤（NK）细胞在控制转移中发挥着至关重要的作用。因此，肿瘤细胞已进化出特定机制来逃避NK细胞介导的免疫监视，从而促进转移和对免疫治疗的抵抗。在本研究中，我们使用小鼠模型研究了静脉注射卡介苗（BCG）在预防膀胱癌细胞肺转移方面的预防和治疗潜力。我们证明，预防性给予BCG可显著减轻肿瘤负担并延长生存期，这主要是通过激活NK细胞实现的。然而，在已形成的肿瘤上给予BCG治疗无效，这可能是由于肿瘤驱动的免疫逃逸机制所致。我们的结果揭示了干扰素-γ（IFN-γ）对肿瘤抗性的作用。体内暴露于IFN-γ的肿瘤细胞对BCG更具抗性，这与免疫检查点分子的过表达相关，而肿瘤细胞中IFN-γ信号通路的破坏部分恢复了BCG的治疗效果。我们的发现凸显了理解肿瘤免疫逃逸机制的重要性，并表明BCG可能是预防膀胱癌肺转移的一种有前景的治疗方法。
